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10491763
Hepatocyte nuclear factor-6: associations between genetic variability and type II diabetes and between genetic variability and estimates of insulin secretion. The transcription factor hepatocyte nuclear factor (HNF)-6 is an upstream regulator of several genes involved in the pathogenesis of maturity-onset diabetes of the young. We therefore tested the hypothesis that variability in the HNF-6 gene is associated with subsets of Type II (non-insulin-dependent) diabetes mellitus and estimates of insulin secretion in glucose tolerant subjects. We cloned the coding region as well as the intron-exon boundaries of the HNF-6 gene. We then examined them on genomic DNA in six MODY probands without mutations in the MODY1, MODY3 and MODY4 genes and in 54 patients with late-onset Type II diabetes by combined single strand conformational polymorphism-heteroduplex analysis followed by direct sequencing of identified variants. An identified missense variant was examined in association studies and genotype-phenotype studies. We identified two silent and one missense (Pro75 Ala) variant. In an association study the allelic frequency of the Pro75Ala polymorphism was 3.2% (95% confidence interval, 1.9-4.5) in 330 patients with Type II diabetes mellitus compared with 4.2% (2.4-6.0) in 238 age-matched glucose tolerant control subjects. Moreover, in studies of 238 middle-aged glucose tolerant subjects, of 226 glucose tolerant offspring of Type II diabetic patients and of 367 young healthy subjects, the carriers of the polymorphism did not differ from non-carriers in glucose induced serum insulin or C-peptide responses. Mutations in the coding region of the HNF-6 gene are not associated with Type II diabetes or with changes in insulin responses to glucose among the Caucasians examined.
[ "Hepatocyte", "nuclear", "factor-6", ":", "associations", "between", "genetic", "variability", "and", "type", "II", "diabetes", "and", "between", "genetic", "variability", "and", "estimates", "of", "insulin", "secretion", ".", "The", "transcription", "factor", "hepatocyte", "nuclear", "factor", "(", "HNF", ")", "-6", "is", "an", "upstream", "regulator", "of", "several", "genes", "involved", "in", "the", "pathogenesis", "of", "maturity-onset", "diabetes", "of", "the", "young", ".", "We", "therefore", "tested", "the", "hypothesis", "that", "variability", "in", "the", "HNF-6", "gene", "is", "associated", "with", "subsets", "of", "Type", "II", "(", "non-insulin-dependent", ")", "diabetes", "mellitus", "and", "estimates", "of", "insulin", "secretion", "in", "glucose", "tolerant", "subjects", ".", "We", "cloned", "the", "coding", "region", "as", "well", "as", "the", "intron-exon", "boundaries", "of", "the", "HNF-6", "gene", ".", "We", "then", "examined", "them", "on", "genomic", "DNA", "in", "six", "MODY", "probands", "without", "mutations", "in", "the", "MODY1", ",", "MODY3", "and", "MODY4", "genes", "and", "in", "54", "patients", "with", "late-onset", "Type", "II", "diabetes", "by", "combined", "single", "strand", "conformational", "polymorphism-heteroduplex", "analysis", "followed", "by", "direct", "sequencing", "of", "identified", "variants", ".", "An", "identified", "missense", "variant", "was", "examined", "in", "association", "studies", "and", "genotype-phenotype", "studies", ".", "We", "identified", "two", "silent", "and", "one", "missense", "(", "Pro75", "Ala", ")", "variant", ".", "In", "an", "association", "study", "the", "allelic", "frequency", "of", "the", "Pro75Ala", "polymorphism", "was", "3.2", "%", "(", "95", "%", "confidence", "interval", ",", "1.9-4.5", ")", "in", "330", "patients", "with", "Type", "II", "diabetes", "mellitus", "compared", "with", "4.2", "%", "(", "2.4-6.0", ")", "in", "238", "age-matched", "glucose", "tolerant", "control", "subjects", ".", "Moreover", ",", "in", "studies", "of", "238", "middle-aged", "glucose", "tolerant", "subjects", ",", "of", "226", "glucose", "tolerant", "offspring", "of", "Type", "II", "diabetic", "patients", "and", "of", "367", "young", "healthy", "subjects", ",", "the", "carriers", "of", "the", "polymorphism", "did", "not", "differ", "from", "non-carriers", "in", "glucose", "induced", "serum", "insulin", "or", "C-peptide", "responses", ".", "Mutations", "in", "the", "coding", "region", "of", "the", "HNF-6", "gene", "are", "not", "associated", "with", "Type", "II", "diabetes", "or", "with", "changes", "in", "insulin", "responses", "to", "glucose", "among", "the", "Caucasians", "examined", "." ]
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10788334
Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer. We have undertaken a hospital-based study, to identify possible BRCA1 and BRCA2 founder mutations in the Polish population. The study group consisted of 66 Polish families with cancer who have at least three related females affected with breast or ovarian cancer and who had cancer diagnosed, in at least one of the three affected females, at age < 50 years. A total of 26 families had both breast and ovarian cancers, 4 families had ovarian cancers only, and 36 families had breast cancers only. Genomic DNA was prepared from the peripheral blood leukocytes of at least one affected woman from each family. The entire coding region of BRCA1 and BRCA2 was screened for the presence of germline mutations, by use of SSCP followed by direct sequencing of observed variants. Mutations were found in 35 (53%) of the 66 families studied. All but one of the mutations were detected within the BRCA1 gene. BRCA1 abnormalities were identified in all four families with ovarian cancer only, in 67% of 27 families with both breast and ovarian cancer, and in 34% of 35 families with breast cancer only. The single family with a BRCA2 mutation had the breast-ovarian cancer syndrome. Seven distinct mutations were identified; five of these occurred in two or more families. In total, recurrent mutations were found in 33 (94%) of the 35 families with detected mutations. Three BRCA1 abnormalities - 5382insC, C61G, and 4153delA - accounted for 51%, 20%, and 11% of the identified mutations, respectively..
[ "Founder", "mutations", "in", "the", "BRCA1", "gene", "in", "Polish", "families", "with", "breast-ovarian", "cancer", ".", "We", "have", "undertaken", "a", "hospital-based", "study", ",", "to", "identify", "possible", "BRCA1", "and", "BRCA2", "founder", "mutations", "in", "the", "Polish", "population", ".", "The", "study", "group", "consisted", "of", "66", "Polish", "families", "with", "cancer", "who", "have", "at", "least", "three", "related", "females", "affected", "with", "breast", "or", "ovarian", "cancer", "and", "who", "had", "cancer", "diagnosed", ",", "in", "at", "least", "one", "of", "the", "three", "affected", "females", ",", "at", "age", "<", "50", "years", ".", "A", "total", "of", "26", "families", "had", "both", "breast", "and", "ovarian", "cancers", ",", "4", "families", "had", "ovarian", "cancers", "only", ",", "and", "36", "families", "had", "breast", "cancers", "only", ".", "Genomic", "DNA", "was", "prepared", "from", "the", "peripheral", "blood", "leukocytes", "of", "at", "least", "one", "affected", "woman", "from", "each", "family", ".", "The", "entire", "coding", "region", "of", "BRCA1", "and", "BRCA2", "was", "screened", "for", "the", "presence", "of", "germline", "mutations", ",", "by", "use", "of", "SSCP", "followed", "by", "direct", "sequencing", "of", "observed", "variants", ".", "Mutations", "were", "found", "in", "35", "(", "53", "%", ")", "of", "the", "66", "families", "studied", ".", "All", "but", "one", "of", "the", "mutations", "were", "detected", "within", "the", "BRCA1", "gene", ".", "BRCA1", "abnormalities", "were", "identified", "in", "all", "four", "families", "with", "ovarian", "cancer", "only", ",", "in", "67", "%", "of", "27", "families", "with", "both", "breast", "and", "ovarian", "cancer", ",", "and", "in", "34", "%", "of", "35", "families", "with", "breast", "cancer", "only", ".", "The", "single", "family", "with", "a", "BRCA2", "mutation", "had", "the", "breast-ovarian", "cancer", "syndrome", ".", "Seven", "distinct", "mutations", "were", "identified", ";", "five", "of", "these", "occurred", "in", "two", "or", "more", "families", ".", "In", "total", ",", "recurrent", "mutations", "were", "found", "in", "33", "(", "94", "%", ")", "of", "the", "35", "families", "with", "detected", "mutations", ".", "Three", "BRCA1", "abnormalities", "-", "5382insC", ",", "C61G", ",", "and", "4153delA", "-", "accounted", "for", "51", "%", ",", "20", "%", ",", "and", "11", "%", "of", "the", "identified", "mutations", ",", "respectively", ".." ]
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11054569
Rab6c, a new member of the rab gene family, is involved in drug resistance in MCF7/AdrR cells. A new Rab6 homolog cDNA, Rab6c, was discovered by a hypermethylated DNA fragment probe that was isolated from a human multidrug resistant (MDR) breast cancer cell line, MCF7/AdrR, by the methylation sensitive-representational difference analysis (MS-RDA) technique. Rab6c was found to be under-expressed in MCF7/AdrR and MES-SA/Dx5 (a human MDR uterine sarcoma cell line) compared with their non-MDR parental cell lines. MCF7/AdrR cells expressing the exogenous Rab6c exhibited less resistance to several anti-cancer drugs, such as doxorubicin (DOX), taxol, vinblastine, and vincristine, than the control cells containing the empty vector. Flow cytometry experiments confirmed that the transfectants' diminished resistance to DOX was caused by increased drug accumulation induced by the exogenous Rab6c. These results indicate that Rab6c is involved in drug resistance in MCF7/AdrR cells.
[ "Rab6c", ",", "a", "new", "member", "of", "the", "rab", "gene", "family", ",", "is", "involved", "in", "drug", "resistance", "in", "MCF7/AdrR", "cells", ".", "A", "new", "Rab6", "homolog", "cDNA", ",", "Rab6c", ",", "was", "discovered", "by", "a", "hypermethylated", "DNA", "fragment", "probe", "that", "was", "isolated", "from", "a", "human", "multidrug", "resistant", "(", "MDR", ")", "breast", "cancer", "cell", "line", ",", "MCF7/AdrR", ",", "by", "the", "methylation", "sensitive-representational", "difference", "analysis", "(", "MS-RDA", ")", "technique", ".", "Rab6c", "was", "found", "to", "be", "under-expressed", "in", "MCF7/AdrR", "and", "MES-SA/Dx5", "(", "a", "human", "MDR", "uterine", "sarcoma", "cell", "line", ")", "compared", "with", "their", "non-MDR", "parental", "cell", "lines", ".", "MCF7/AdrR", "cells", "expressing", "the", "exogenous", "Rab6c", "exhibited", "less", "resistance", "to", "several", "anti-cancer", "drugs", ",", "such", "as", "doxorubicin", "(", "DOX", ")", ",", "taxol", ",", "vinblastine", ",", "and", "vincristine", ",", "than", "the", "control", "cells", "containing", "the", "empty", "vector", ".", "Flow", "cytometry", "experiments", "confirmed", "that", "the", "transfectants", "'", "diminished", "resistance", "to", "DOX", "was", "caused", "by", "increased", "drug", "accumulation", "induced", "by", "the", "exogenous", "Rab6c", ".", "These", "results", "indicate", "that", "Rab6c", "is", "involved", "in", "drug", "resistance", "in", "MCF7/AdrR", "cells", "." ]
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1353340
Late-onset metachromatic leukodystrophy: molecular pathology in two siblings. We report on a new allele at the arylsulfatase A (ARSA) locus causing late-onset metachromatic leukodystrophy (MLD). In that allele arginine84, a residue that is highly conserved in the arylsulfatase gene family, is replaced by glutamine. In contrast to alleles that cause early-onset MLD, the arginine84 to glutamine substitution is associated with some residual ARSA activity. A comparison of genotypes, ARSA activities, and clinical data on 4 individuals carrying the allele of 81 patients with MLD examined, further validates the concept that different degrees of residual ARSA activity are the basis of phenotypical variation in MLD..
[ "Late-onset", "metachromatic", "leukodystrophy", ":", "molecular", "pathology", "in", "two", "siblings", ".", "We", "report", "on", "a", "new", "allele", "at", "the", "arylsulfatase", "A", "(", "ARSA", ")", "locus", "causing", "late-onset", "metachromatic", "leukodystrophy", "(", "MLD", ")", ".", "In", "that", "allele", "arginine84", ",", "a", "residue", "that", "is", "highly", "conserved", "in", "the", "arylsulfatase", "gene", "family", ",", "is", "replaced", "by", "glutamine", ".", "In", "contrast", "to", "alleles", "that", "cause", "early-onset", "MLD", ",", "the", "arginine84", "to", "glutamine", "substitution", "is", "associated", "with", "some", "residual", "ARSA", "activity", ".", "A", "comparison", "of", "genotypes", ",", "ARSA", "activities", ",", "and", "clinical", "data", "on", "4", "individuals", "carrying", "the", "allele", "of", "81", "patients", "with", "MLD", "examined", ",", "further", "validates", "the", "concept", "that", "different", "degrees", "of", "residual", "ARSA", "activity", "are", "the", "basis", "of", "phenotypical", "variation", "in", "MLD", ".." ]
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15099351
Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is at a locus for autosomal dominant hypercholesterolemia, and recent data indicate that the PCSK9 gene is involved in cholesterol biosynthesis. Mutations within this gene have previously been found to segregate with hypercholesterolemia. In this study, DNA sequencing of the 12 exons of the PCSK9 gene has been performed in 51 Norwegian subjects with a clinical diagnosis of familial hypercholesterolemia where mutations in the low-density lipoprotein receptor gene and mutation R3500Q in the apolipoprotein B-100 gene had been excluded. Two novel missense mutations were detected in the catalytic subdomain of the PCSK9 gene. Two patients were heterozygotes for D374Y, and one patient was a double heterozygote for D374Y and N157K. D374Y segregated with hypercholesterolemia in the two former families where family members were available for study. Our findings support the notion that mutations in the PCSK9 gene cause autosomal dominant hypercholesterolemia.
[ "Mutations", "in", "the", "PCSK9", "gene", "in", "Norwegian", "subjects", "with", "autosomal", "dominant", "hypercholesterolemia", ".", "Proprotein", "convertase", "subtilisin/kexin", "type", "9", "(", "PCSK9", ")", "is", "at", "a", "locus", "for", "autosomal", "dominant", "hypercholesterolemia", ",", "and", "recent", "data", "indicate", "that", "the", "PCSK9", "gene", "is", "involved", "in", "cholesterol", "biosynthesis", ".", "Mutations", "within", "this", "gene", "have", "previously", "been", "found", "to", "segregate", "with", "hypercholesterolemia", ".", "In", "this", "study", ",", "DNA", "sequencing", "of", "the", "12", "exons", "of", "the", "PCSK9", "gene", "has", "been", "performed", "in", "51", "Norwegian", "subjects", "with", "a", "clinical", "diagnosis", "of", "familial", "hypercholesterolemia", "where", "mutations", "in", "the", "low-density", "lipoprotein", "receptor", "gene", "and", "mutation", "R3500Q", "in", "the", "apolipoprotein", "B-100", "gene", "had", "been", "excluded", ".", "Two", "novel", "missense", "mutations", "were", "detected", "in", "the", "catalytic", "subdomain", "of", "the", "PCSK9", "gene", ".", "Two", "patients", "were", "heterozygotes", "for", "D374Y", ",", "and", "one", "patient", "was", "a", "double", "heterozygote", "for", "D374Y", "and", "N157K", ".", "D374Y", "segregated", "with", "hypercholesterolemia", "in", "the", "two", "former", "families", "where", "family", "members", "were", "available", "for", "study", ".", "Our", "findings", "support", "the", "notion", "that", "mutations", "in", "the", "PCSK9", "gene", "cause", "autosomal", "dominant", "hypercholesterolemia", "." ]
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16005363
Identification of a novel WFS1 mutation (AFF344-345ins) in Japanese patients with Wolfram syndrome. Wolfram syndrome (WFS) is an autosomal recessive disorder characterized by early onset diabetes mellitus, progressive optic atrophy, sensorineural deafness and diabetes insipidus. Affected individuals may also have renal tract abnormalities as well as neurogical and psychiatric syndromes. WFS1 encoding a transmembrane protein was identified as the gene responsible for WFS. We report herein a Japanese family, of which two members had this syndrome. In the WFS1 gene of these patients, we identified a novel mutation, a nine nucleotide insertion (AFF344-345ins). In addition, one of these patients had preclinical hypopituitarism, which is an unusual feature of WFS. As only the two family members homozygous for the mutation showed WFS, these data support the notion that this mutation is the cause of WFS.
[ "Identification", "of", "a", "novel", "WFS1", "mutation", "(", "AFF344-345ins", ")", "in", "Japanese", "patients", "with", "Wolfram", "syndrome", ".", "Wolfram", "syndrome", "(", "WFS", ")", "is", "an", "autosomal", "recessive", "disorder", "characterized", "by", "early", "onset", "diabetes", "mellitus", ",", "progressive", "optic", "atrophy", ",", "sensorineural", "deafness", "and", "diabetes", "insipidus", ".", "Affected", "individuals", "may", "also", "have", "renal", "tract", "abnormalities", "as", "well", "as", "neurogical", "and", "psychiatric", "syndromes", ".", "WFS1", "encoding", "a", "transmembrane", "protein", "was", "identified", "as", "the", "gene", "responsible", "for", "WFS", ".", "We", "report", "herein", "a", "Japanese", "family", ",", "of", "which", "two", "members", "had", "this", "syndrome", ".", "In", "the", "WFS1", "gene", "of", "these", "patients", ",", "we", "identified", "a", "novel", "mutation", ",", "a", "nine", "nucleotide", "insertion", "(", "AFF344-345ins", ")", ".", "In", "addition", ",", "one", "of", "these", "patients", "had", "preclinical", "hypopituitarism", ",", "which", "is", "an", "unusual", "feature", "of", "WFS", ".", "As", "only", "the", "two", "family", "members", "homozygous", "for", "the", "mutation", "showed", "WFS", ",", "these", "data", "support", "the", "notion", "that", "this", "mutation", "is", "the", "cause", "of", "WFS", "." ]
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16200390
A genetic analysis of serotonergic biosynthetic and metabolic enzymes in migraine using a DNA pooling approach. Migraine is a common debilitating primary headache disorder with significant mental, physical and social health implications. The brain neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) is involved in nociceptive pathways and has been implicated in the pathophysiology of migraine. With few genetic studies investigating biosynthetic and metabolic enzymes governing the rate of 5-HT activity and their relationship to migraine, it was the objective of this study to assess genetic variants within the human tryptophan hydroxylase (TPH), amino acid decarboxylase (AADC) and monoamine oxidase A (MAOA) genes in migraine susceptibility. This objective was undertaken using a high-throughput DNA pooling experimental design, which proved to be a very accurate, sensitive and specific method of estimating allele frequencies for single nucleotide polymorphism, insertion deletion and variable number tandem repeat loci. Application of DNA pooling to a wide array of genetic loci provides greater scope in the assessment of population-based genetic association study designs. Despite the application of this high-throughput genotyping method, negative results from the two-stage DNA pooling design used to screen loci within the TPH, AADC and MAOA genes did not support their role in migraine susceptibility.
[ "A", "genetic", "analysis", "of", "serotonergic", "biosynthetic", "and", "metabolic", "enzymes", "in", "migraine", "using", "a", "DNA", "pooling", "approach", ".", "Migraine", "is", "a", "common", "debilitating", "primary", "headache", "disorder", "with", "significant", "mental", ",", "physical", "and", "social", "health", "implications", ".", "The", "brain", "neurotransmitter", "5-hydroxytryptamine", "(", "5-HT", ";", "serotonin", ")", "is", "involved", "in", "nociceptive", "pathways", "and", "has", "been", "implicated", "in", "the", "pathophysiology", "of", "migraine", ".", "With", "few", "genetic", "studies", "investigating", "biosynthetic", "and", "metabolic", "enzymes", "governing", "the", "rate", "of", "5-HT", "activity", "and", "their", "relationship", "to", "migraine", ",", "it", "was", "the", "objective", "of", "this", "study", "to", "assess", "genetic", "variants", "within", "the", "human", "tryptophan", "hydroxylase", "(", "TPH", ")", ",", "amino", "acid", "decarboxylase", "(", "AADC", ")", "and", "monoamine", "oxidase", "A", "(", "MAOA", ")", "genes", "in", "migraine", "susceptibility", ".", "This", "objective", "was", "undertaken", "using", "a", "high-throughput", "DNA", "pooling", "experimental", "design", ",", "which", "proved", "to", "be", "a", "very", "accurate", ",", "sensitive", "and", "specific", "method", "of", "estimating", "allele", "frequencies", "for", "single", "nucleotide", "polymorphism", ",", "insertion", "deletion", "and", "variable", "number", "tandem", "repeat", "loci", ".", "Application", "of", "DNA", "pooling", "to", "a", "wide", "array", "of", "genetic", "loci", "provides", "greater", "scope", "in", "the", "assessment", "of", "population-based", "genetic", "association", "study", "designs", ".", "Despite", "the", "application", "of", "this", "high-throughput", "genotyping", "method", ",", "negative", "results", "from", "the", "two-stage", "DNA", "pooling", "design", "used", "to", "screen", "loci", "within", "the", "TPH", ",", "AADC", "and", "MAOA", "genes", "did", "not", "support", "their", "role", "in", "migraine", "susceptibility", "." ]
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16596970
Pilocarpine seizures cause age-dependent impairment in auditory location discrimination. Children who have status epilepticus have continuous or rapidly repeating seizures that may be life-threatening and may cause life-long changes in brain and behavior. The extent to which status epilepticus causes deficits in auditory discrimination is unknown. A naturalistic auditory location discrimination method was used to evaluate this question using an animal model of status epilepticus. Male Sprague-Dawley rats were injected with saline on postnatal day (P) 20, or a convulsant dose of pilocarpine on P20 or P45. Pilocarpine on either day induced status epilepticus; status epilepticus at P45 resulted in CA3 cell loss and spontaneous seizures, whereas P20 rats had no cell loss or spontaneous seizures. Mature rats were trained with sound-source location and sound-silence discriminations. Control (saline P20) rats acquired both discriminations immediately. In status epilepticus (P20) rats, acquisition of the sound-source location discrimination was moderately impaired. Status epilepticus (P45) rats failed to acquire either sound-source location or sound-silence discriminations. Status epilepticus in rat causes an age-dependent, long-term impairment in auditory discrimination. This impairment may explain one cause of impaired auditory location discrimination in humans.
[ "Pilocarpine", "seizures", "cause", "age-dependent", "impairment", "in", "auditory", "location", "discrimination", ".", "Children", "who", "have", "status", "epilepticus", "have", "continuous", "or", "rapidly", "repeating", "seizures", "that", "may", "be", "life-threatening", "and", "may", "cause", "life-long", "changes", "in", "brain", "and", "behavior", ".", "The", "extent", "to", "which", "status", "epilepticus", "causes", "deficits", "in", "auditory", "discrimination", "is", "unknown", ".", "A", "naturalistic", "auditory", "location", "discrimination", "method", "was", "used", "to", "evaluate", "this", "question", "using", "an", "animal", "model", "of", "status", "epilepticus", ".", "Male", "Sprague-Dawley", "rats", "were", "injected", "with", "saline", "on", "postnatal", "day", "(", "P", ")", "20", ",", "or", "a", "convulsant", "dose", "of", "pilocarpine", "on", "P20", "or", "P45", ".", "Pilocarpine", "on", "either", "day", "induced", "status", "epilepticus", ";", "status", "epilepticus", "at", "P45", "resulted", "in", "CA3", "cell", "loss", "and", "spontaneous", "seizures", ",", "whereas", "P20", "rats", "had", "no", "cell", "loss", "or", "spontaneous", "seizures", ".", "Mature", "rats", "were", "trained", "with", "sound-source", "location", "and", "sound-silence", "discriminations", ".", "Control", "(", "saline", "P20", ")", "rats", "acquired", "both", "discriminations", "immediately", ".", "In", "status", "epilepticus", "(", "P20", ")", "rats", ",", "acquisition", "of", "the", "sound-source", "location", "discrimination", "was", "moderately", "impaired", ".", "Status", "epilepticus", "(", "P45", ")", "rats", "failed", "to", "acquire", "either", "sound-source", "location", "or", "sound-silence", "discriminations", ".", "Status", "epilepticus", "in", "rat", "causes", "an", "age-dependent", ",", "long-term", "impairment", "in", "auditory", "discrimination", ".", "This", "impairment", "may", "explain", "one", "cause", "of", "impaired", "auditory", "location", "discrimination", "in", "humans", "." ]
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17683901
An improved tetra-primer PCR approach for the detection of the FGFR3 G380R mutation responsible for achondroplasia. Achondroplasia is the most common form of dwarfism and has an incidence of approximately 1/7500. In more than 98% of cases, the disease is associated with a G to A or G to C substitution at nucleotide position 1138 (p.G380R) of the fibroblast growth factor receptor 3 (FGFR3) gene. We have developed a sensitive single tube tetra-primer PCR assay to detect both the c.1138G>A and c.1138G>C mutations and can successfully distinguish DNA samples that are homozygous and heterozygous for the c.1138G>A mutation. Titration studies showed that the assay could reliably detect one copy of the mutant allele in a mix of 100 wild-type alleles. The assay has been tested in 50 healthy controls, 3 known patients with achondroplasia, and 5 amniotic fluids suspected of having achondroplasia and for whom we had previously determined the genotypes for the c.1138G>A mutation by PCR-RFLP. We have observed complete concordance between methods. Our tetra-primer PCR assay is sensitive, low-cost, and easy to use method for FGFR3 p.G380R genotyping, which could be used even in "low-tech" laboratories.
[ "An", "improved", "tetra-primer", "PCR", "approach", "for", "the", "detection", "of", "the", "FGFR3", "G380R", "mutation", "responsible", "for", "achondroplasia", ".", "Achondroplasia", "is", "the", "most", "common", "form", "of", "dwarfism", "and", "has", "an", "incidence", "of", "approximately", "1/7500", ".", "In", "more", "than", "98", "%", "of", "cases", ",", "the", "disease", "is", "associated", "with", "a", "G", "to", "A", "or", "G", "to", "C", "substitution", "at", "nucleotide", "position", "1138", "(", "p.G380R", ")", "of", "the", "fibroblast", "growth", "factor", "receptor", "3", "(", "FGFR3", ")", "gene", ".", "We", "have", "developed", "a", "sensitive", "single", "tube", "tetra-primer", "PCR", "assay", "to", "detect", "both", "the", "c.1138G", ">", "A", "and", "c.1138G", ">", "C", "mutations", "and", "can", "successfully", "distinguish", "DNA", "samples", "that", "are", "homozygous", "and", "heterozygous", "for", "the", "c.1138G", ">", "A", "mutation", ".", "Titration", "studies", "showed", "that", "the", "assay", "could", "reliably", "detect", "one", "copy", "of", "the", "mutant", "allele", "in", "a", "mix", "of", "100", "wild-type", "alleles", ".", "The", "assay", "has", "been", "tested", "in", "50", "healthy", "controls", ",", "3", "known", "patients", "with", "achondroplasia", ",", "and", "5", "amniotic", "fluids", "suspected", "of", "having", "achondroplasia", "and", "for", "whom", "we", "had", "previously", "determined", "the", "genotypes", "for", "the", "c.1138G", ">", "A", "mutation", "by", "PCR-RFLP", ".", "We", "have", "observed", "complete", "concordance", "between", "methods", ".", "Our", "tetra-primer", "PCR", "assay", "is", "sensitive", ",", "low-cost", ",", "and", "easy", "to", "use", "method", "for", "FGFR3", "p.G380R", "genotyping", ",", "which", "could", "be", "used", "even", "in", "``", "low-tech", "''", "laboratories", "." ]
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18166824
Genetic investigation of four meiotic genes in women with premature ovarian failure. OBJECTIVE: The goal of this study was to determine whether mutations of meiotic genes, such as disrupted meiotic cDNA (DMC1), MutS homolog (MSH4), MSH5, and S. cerevisiae homolog (SPO11), were associated with premature ovarian failure (POF). DESIGN: Case-control study. METHODS: Blood sampling, karyotype, hormonal dosage, ultrasound, and ovarian biopsy were carried out on most patients. However, the main outcome measure was the sequencing of genomic DNA from peripheral blood samples of 41 women with POF and 36 fertile women (controls). RESULTS: A single heterozygous missense mutation, substitution of a cytosine residue with thymidine in exon 2 of MSH5, was found in two Caucasian women in whom POF developed at 18 and 36 years of age. This mutation resulted in replacement of a non-polar amino acid (proline) with a polar amino acid (serine) at position 29 (P29S). Neither 36 control women nor 39 other patients with POF possessed this genetic perturbation. Another POF patient of African origin showed a homozygous nucleotide change in the tenth of DMC1 gene that led to an alteration of the amino acid composition of the protein (M200V). CONCLUSIONS: The symptoms of infertility observed in the DMC1 homozygote mutation carrier and in both patients with a heterozygous substitution in exon 2 of the MSH5 gene provide indirect evidence of the role of genes involved in meiotic recombination in the regulation of ovarian function. MSH5 and DMC1 mutations may be one explanation for POF, albeit uncommon.
[ "Genetic", "investigation", "of", "four", "meiotic", "genes", "in", "women", "with", "premature", "ovarian", "failure", ".", "OBJECTIVE", ":", "The", "goal", "of", "this", "study", "was", "to", "determine", "whether", "mutations", "of", "meiotic", "genes", ",", "such", "as", "disrupted", "meiotic", "cDNA", "(", "DMC1", ")", ",", "MutS", "homolog", "(", "MSH4", ")", ",", "MSH5", ",", "and", "S.", "cerevisiae", "homolog", "(", "SPO11", ")", ",", "were", "associated", "with", "premature", "ovarian", "failure", "(", "POF", ")", ".", "DESIGN", ":", "Case-control", "study", ".", "METHODS", ":", "Blood", "sampling", ",", "karyotype", ",", "hormonal", "dosage", ",", "ultrasound", ",", "and", "ovarian", "biopsy", "were", "carried", "out", "on", "most", "patients", ".", "However", ",", "the", "main", "outcome", "measure", "was", "the", "sequencing", "of", "genomic", "DNA", "from", "peripheral", "blood", "samples", "of", "41", "women", "with", "POF", "and", "36", "fertile", "women", "(", "controls", ")", ".", "RESULTS", ":", "A", "single", "heterozygous", "missense", "mutation", ",", "substitution", "of", "a", "cytosine", "residue", "with", "thymidine", "in", "exon", "2", "of", "MSH5", ",", "was", "found", "in", "two", "Caucasian", "women", "in", "whom", "POF", "developed", "at", "18", "and", "36", "years", "of", "age", ".", "This", "mutation", "resulted", "in", "replacement", "of", "a", "non-polar", "amino", "acid", "(", "proline", ")", "with", "a", "polar", "amino", "acid", "(", "serine", ")", "at", "position", "29", "(", "P29S", ")", ".", "Neither", "36", "control", "women", "nor", "39", "other", "patients", "with", "POF", "possessed", "this", "genetic", "perturbation", ".", "Another", "POF", "patient", "of", "African", "origin", "showed", "a", "homozygous", "nucleotide", "change", "in", "the", "tenth", "of", "DMC1", "gene", "that", "led", "to", "an", "alteration", "of", "the", "amino", "acid", "composition", "of", "the", "protein", "(", "M200V", ")", ".", "CONCLUSIONS", ":", "The", "symptoms", "of", "infertility", "observed", "in", "the", "DMC1", "homozygote", "mutation", "carrier", "and", "in", "both", "patients", "with", "a", "heterozygous", "substitution", "in", "exon", "2", "of", "the", "MSH5", "gene", "provide", "indirect", "evidence", "of", "the", "role", "of", "genes", "involved", "in", "meiotic", "recombination", "in", "the", "regulation", "of", "ovarian", "function", ".", "MSH5", "and", "DMC1", "mutations", "may", "be", "one", "explanation", "for", "POF", ",", "albeit", "uncommon", "." ]
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18408250
A single nucleotide polymorphism in the IRF5 promoter region is associated with susceptibility to rheumatoid arthritis in the Japanese population. OBJECTIVES: Interferon regulatory factor 5 (IRF5) is a member of the IRF family of transcription factors, which regulate the production of proinflammatory cytokines. Polymorphisms in the IRF5 gene have been associated with susceptibility to systemic lupus erythaematosus (SLE) in Caucasian and Asian populations, but their involvement in other autoimmune diseases is still uncertain. Here, we assessed the genetic role of IRF5 in susceptibility to rheumatoid arthritis (RA) in Japanese subjects. METHODS: We selected 13 single nucleotide polymorphisms (SNPs) and a CGGGG insertion-deletion polymorphism in the IRF5 gene. We performed 2 sets of case-control comparisons using Japanese subjects (first set: 830 patients with RA and 658 controls; second set: 1112 patients with RA and 940 controls), and then performed a stratified analysis using human leukocyte antigen (HLA)-DRB1 shared epitope (SE) status. We genotyped the SNPs using TaqMan assays. RESULTS: A significant association of the rs729302 A allele with RA susceptibility was found in both sets (odds ratio (OR) 1.22, 95% CI 1.09 to 1.35, p<0.001 in the combined analysis). When the patients were stratified by the SE, the rs729302 A allele was found to confer increased risk to RA in patients that were SE negative (OR 1.50, 95% CI 1.17 to 1.92, p = 0.001) as compared with patients carrying the SE (OR 1.11, 95% CI 0.93 to 1.33, p = 0.24). In both sets, no genotyped polymorphisms were significantly associated with RA susceptibility, but rs729302 was significantly associated. CONCLUSIONS: These findings indicate that the promoter polymorphism of IRF5 is a genetic factor conferring predisposition to RA, and that it contributes considerably to disease pathogenesis in patients that were SE negative.
[ "A", "single", "nucleotide", "polymorphism", "in", "the", "IRF5", "promoter", "region", "is", "associated", "with", "susceptibility", "to", "rheumatoid", "arthritis", "in", "the", "Japanese", "population", ".", "OBJECTIVES", ":", "Interferon", "regulatory", "factor", "5", "(", "IRF5", ")", "is", "a", "member", "of", "the", "IRF", "family", "of", "transcription", "factors", ",", "which", "regulate", "the", "production", "of", "proinflammatory", "cytokines", ".", "Polymorphisms", "in", "the", "IRF5", "gene", "have", "been", "associated", "with", "susceptibility", "to", "systemic", "lupus", "erythaematosus", "(", "SLE", ")", "in", "Caucasian", "and", "Asian", "populations", ",", "but", "their", "involvement", "in", "other", "autoimmune", "diseases", "is", "still", "uncertain", ".", "Here", ",", "we", "assessed", "the", "genetic", "role", "of", "IRF5", "in", "susceptibility", "to", "rheumatoid", "arthritis", "(", "RA", ")", "in", "Japanese", "subjects", ".", "METHODS", ":", "We", "selected", "13", "single", "nucleotide", "polymorphisms", "(", "SNPs", ")", "and", "a", "CGGGG", "insertion-deletion", "polymorphism", "in", "the", "IRF5", "gene", ".", "We", "performed", "2", "sets", "of", "case-control", "comparisons", "using", "Japanese", "subjects", "(", "first", "set", ":", "830", "patients", "with", "RA", "and", "658", "controls", ";", "second", "set", ":", "1112", "patients", "with", "RA", "and", "940", "controls", ")", ",", "and", "then", "performed", "a", "stratified", "analysis", "using", "human", "leukocyte", "antigen", "(", "HLA", ")", "-DRB1", "shared", "epitope", "(", "SE", ")", "status", ".", "We", "genotyped", "the", "SNPs", "using", "TaqMan", "assays", ".", "RESULTS", ":", "A", "significant", "association", "of", "the", "rs729302", "A", "allele", "with", "RA", "susceptibility", "was", "found", "in", "both", "sets", "(", "odds", "ratio", "(", "OR", ")", "1.22", ",", "95", "%", "CI", "1.09", "to", "1.35", ",", "p", "<", "0.001", "in", "the", "combined", "analysis", ")", ".", "When", "the", "patients", "were", "stratified", "by", "the", "SE", ",", "the", "rs729302", "A", "allele", "was", "found", "to", "confer", "increased", "risk", "to", "RA", "in", "patients", "that", "were", "SE", "negative", "(", "OR", "1.50", ",", "95", "%", "CI", "1.17", "to", "1.92", ",", "p", "=", "0.001", ")", "as", "compared", "with", "patients", "carrying", "the", "SE", "(", "OR", "1.11", ",", "95", "%", "CI", "0.93", "to", "1.33", ",", "p", "=", "0.24", ")", ".", "In", "both", "sets", ",", "no", "genotyped", "polymorphisms", "were", "significantly", "associated", "with", "RA", "susceptibility", ",", "but", "rs729302", "was", "significantly", "associated", ".", "CONCLUSIONS", ":", "These", "findings", "indicate", "that", "the", "promoter", "polymorphism", "of", "IRF5", "is", "a", "genetic", "factor", "conferring", "predisposition", "to", "RA", ",", "and", "that", "it", "contributes", "considerably", "to", "disease", "pathogenesis", "in", "patients", "that", "were", "SE", "negative", "." ]
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18439317
Association between promoter -1607 polymorphism of MMP1 and lumbar disc disease in Southern Chinese. BACKGROUND: Matrix metalloproteinases (MMPs) are involved in the degradation of the extracellular matrix of the intervertebral disc. A SNP for guanine insertion/deletion (G/D), the -1607 promoter polymorphism, of the MMP1 gene was found significantly affecting promoter activity and corresponding transcription level. Hence it is a good candidate for genetic studies in DDD. METHODS: Southern Chinese volunteers between 18 and 55 years were recruited from the population. DDD in the lumbar spine was defined by MRI using Schneiderman's classification. Genomic DNA was isolated from the leukocytes and genotyping was performed using the Sequenom platform. Association and Hardy-Weinberg equilibrium checking were assessed by Chi-square test and Mann-Whitney U test. RESULTS: Our results showed substantial evidence of association between -1607 promoter polymorphism of MMP1 and DDD in the Southern Chinese subjects. D allelic was significantly associated with DDD (p value = 0.027, odds ratio = 1.41 with 95% CI = 1.04-1.90) while Genotypic association on the presence of D allele was also significantly associated with DDD (p value = 0.046, odds ratio = 1.50 with 95% CI = 1.01-2.24). Further age stratification showed significant genotypic as well as allelic association in the group of over 40 years (genotypic: p value = 0.035, odds ratio = 1.617 with 95% CI = 1.033-2.529; allelic: p value = 0.033, odds ratio = 1.445 with 95% CI = 1.029-2.029). Disc bulge, annular tears and the Schmorl's nodes were not associated with the D allele. CONCLUSION: We demonstrated that individuals with the presence of D allele for the -1607 promoter polymorphism of MMP1 are about 1.5 times more susceptible to develop DDD when compared with those having G allele only. Further association was identified in individuals over 40 years of age. Disc bulge, annular tear as well as Schmorl's nodes were not associated with this polymorphism.
[ "Association", "between", "promoter", "-1607", "polymorphism", "of", "MMP1", "and", "lumbar", "disc", "disease", "in", "Southern", "Chinese", ".", "BACKGROUND", ":", "Matrix", "metalloproteinases", "(", "MMPs", ")", "are", "involved", "in", "the", "degradation", "of", "the", "extracellular", "matrix", "of", "the", "intervertebral", "disc", ".", "A", "SNP", "for", "guanine", "insertion/deletion", "(", "G/D", ")", ",", "the", "-1607", "promoter", "polymorphism", ",", "of", "the", "MMP1", "gene", "was", "found", "significantly", "affecting", "promoter", "activity", "and", "corresponding", "transcription", "level", ".", "Hence", "it", "is", "a", "good", "candidate", "for", "genetic", "studies", "in", "DDD", ".", "METHODS", ":", "Southern", "Chinese", "volunteers", "between", "18", "and", "55", "years", "were", "recruited", "from", "the", "population", ".", "DDD", "in", "the", "lumbar", "spine", "was", "defined", "by", "MRI", "using", "Schneiderman", "'s", "classification", ".", "Genomic", "DNA", "was", "isolated", "from", "the", "leukocytes", "and", "genotyping", "was", "performed", "using", "the", "Sequenom", "platform", ".", "Association", "and", "Hardy-Weinberg", "equilibrium", "checking", "were", "assessed", "by", "Chi-square", "test", "and", "Mann-Whitney", "U", "test", ".", "RESULTS", ":", "Our", "results", "showed", "substantial", "evidence", "of", "association", "between", "-1607", "promoter", "polymorphism", "of", "MMP1", "and", "DDD", "in", "the", "Southern", "Chinese", "subjects", ".", "D", "allelic", "was", "significantly", "associated", "with", "DDD", "(", "p", "value", "=", "0.027", ",", "odds", "ratio", "=", "1.41", "with", "95", "%", "CI", "=", "1.04-1.90", ")", "while", "Genotypic", "association", "on", "the", "presence", "of", "D", "allele", "was", "also", "significantly", "associated", "with", "DDD", "(", "p", "value", "=", "0.046", ",", "odds", "ratio", "=", "1.50", "with", "95", "%", "CI", "=", "1.01-2.24", ")", ".", "Further", "age", "stratification", "showed", "significant", "genotypic", "as", "well", "as", "allelic", "association", "in", "the", "group", "of", "over", "40", "years", "(", "genotypic", ":", "p", "value", "=", "0.035", ",", "odds", "ratio", "=", "1.617", "with", "95", "%", "CI", "=", "1.033-2.529", ";", "allelic", ":", "p", "value", "=", "0.033", ",", "odds", "ratio", "=", "1.445", "with", "95", "%", "CI", "=", "1.029-2.029", ")", ".", "Disc", "bulge", ",", "annular", "tears", "and", "the", "Schmorl", "'s", "nodes", "were", "not", "associated", "with", "the", "D", "allele", ".", "CONCLUSION", ":", "We", "demonstrated", "that", "individuals", "with", "the", "presence", "of", "D", "allele", "for", "the", "-1607", "promoter", "polymorphism", "of", "MMP1", "are", "about", "1.5", "times", "more", "susceptible", "to", "develop", "DDD", "when", "compared", "with", "those", "having", "G", "allele", "only", ".", "Further", "association", "was", "identified", "in", "individuals", "over", "40", "years", "of", "age", ".", "Disc", "bulge", ",", "annular", "tear", "as", "well", "as", "Schmorl", "'s", "nodes", "were", "not", "associated", "with", "this", "polymorphism", "." ]
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18681856
Expanding clinical spectrum of non-autoimmune hyperthyroidism due to an activating germline mutation, p.M453T, in the thyrotropin receptor gene. OBJECTIVE: To describe clinical and genetic features of a Thai family with non-autoimmune hyperthyroidism (NAH) caused by an activating germline mutation in the thyrotropin receptor (TSHR) gene. PATIENTS: Three affected individuals from the same family (a father and his two children) were studied. Clinical and imaging findings were reviewed and compared. GENETIC ANALYSIS: Genomic DNA was extracted from peripheral blood leukocytes and mutation analysis of the entire coding sequence of the TSHR gene was performed in both children and their parents by direct DNA sequencing. RESULTS: A heterozygous germline T to C transition in exon 10 of the TSHR gene (c.1358T-->C) resulting in the substitution of methionine (ATG) by threonine (ACG) at codon 453 (p.M453T) was identified in the father and his two children. They presented with different clinical severity and variable age of onset. In addition to hyperthyroidism, ventriculomegaly and bilateral shortening of the fifth metacarpal bones and the middle phalanges of the fifth fingers were consistently found in all affected individuals. CONCLUSIONS: Ventriculomegaly and bilateral shortening of the fifth metacarpal bones and the middle phalanges of the fifth fingers might be characteristic features of NAH because of an activating TSHR germline mutation. In addition, the shortening of the middle phalanges of the fifth fingers has never been previously described, expanding the phenotypic spectrum of the disease.
[ "Expanding", "clinical", "spectrum", "of", "non-autoimmune", "hyperthyroidism", "due", "to", "an", "activating", "germline", "mutation", ",", "p.M453T", ",", "in", "the", "thyrotropin", "receptor", "gene", ".", "OBJECTIVE", ":", "To", "describe", "clinical", "and", "genetic", "features", "of", "a", "Thai", "family", "with", "non-autoimmune", "hyperthyroidism", "(", "NAH", ")", "caused", "by", "an", "activating", "germline", "mutation", "in", "the", "thyrotropin", "receptor", "(", "TSHR", ")", "gene", ".", "PATIENTS", ":", "Three", "affected", "individuals", "from", "the", "same", "family", "(", "a", "father", "and", "his", "two", "children", ")", "were", "studied", ".", "Clinical", "and", "imaging", "findings", "were", "reviewed", "and", "compared", ".", "GENETIC", "ANALYSIS", ":", "Genomic", "DNA", "was", "extracted", "from", "peripheral", "blood", "leukocytes", "and", "mutation", "analysis", "of", "the", "entire", "coding", "sequence", "of", "the", "TSHR", "gene", "was", "performed", "in", "both", "children", "and", "their", "parents", "by", "direct", "DNA", "sequencing", ".", "RESULTS", ":", "A", "heterozygous", "germline", "T", "to", "C", "transition", "in", "exon", "10", "of", "the", "TSHR", "gene", "(", "c.1358T", "--", ">", "C", ")", "resulting", "in", "the", "substitution", "of", "methionine", "(", "ATG", ")", "by", "threonine", "(", "ACG", ")", "at", "codon", "453", "(", "p.M453T", ")", "was", "identified", "in", "the", "father", "and", "his", "two", "children", ".", "They", "presented", "with", "different", "clinical", "severity", "and", "variable", "age", "of", "onset", ".", "In", "addition", "to", "hyperthyroidism", ",", "ventriculomegaly", "and", "bilateral", "shortening", "of", "the", "fifth", "metacarpal", "bones", "and", "the", "middle", "phalanges", "of", "the", "fifth", "fingers", "were", "consistently", "found", "in", "all", "affected", "individuals", ".", "CONCLUSIONS", ":", "Ventriculomegaly", "and", "bilateral", "shortening", "of", "the", "fifth", "metacarpal", "bones", "and", "the", "middle", "phalanges", "of", "the", "fifth", "fingers", "might", "be", "characteristic", "features", "of", "NAH", "because", "of", "an", "activating", "TSHR", "germline", "mutation", ".", "In", "addition", ",", "the", "shortening", "of", "the", "middle", "phalanges", "of", "the", "fifth", "fingers", "has", "never", "been", "previously", "described", ",", "expanding", "the", "phenotypic", "spectrum", "of", "the", "disease", "." ]
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19728177
Prolonged hypothermia as a bridge to recovery for cerebral edema and intracranial hypertension associated with fulminant hepatic failure. BACKGROUND: To review evidence-based treatment options in patients with cerebral edema complicating fulminant hepatic failure (FHF) and discuss the potential applications of hypothermia. METHOD: Case-based observations from a medical intensive care unit (MICU) in a tertiary care facility in a 27-year-old female with FHF from acetaminophen and resultant cerebral edema. RESULTS: Our patient was admitted to the MICU after being found unresponsive with presumed toxicity from acetaminophen which was ingested over a 2-day period. The patient had depressed of mental status lasting at least 24 h prior to admission. Initial evaluation confirmed FHF from acetaminophen and cerebral edema. The patient was treated with hyperosmolar therapy, hyperventilation, sedation, and chemical paralysis. Her intracranial pressure remained elevated despite maximal medical therapy. We then initiated therapeutic hypothermia which was continued for 5 days. At re-warming, patient had resolution of her cerebral edema and intracranial hypertension. At discharge, she had complete recovery of neurological and hepatic functions. CONCLUSION: In patients with FHF and cerebral edema from acetaminophen overdose, prolonged therapeutic hypothermia could potentially be used as a life saving therapy and a bridge to hepatic and neurological recovery. A clinical trial of hypothermia in patients with this condition is warranted.
[ "Prolonged", "hypothermia", "as", "a", "bridge", "to", "recovery", "for", "cerebral", "edema", "and", "intracranial", "hypertension", "associated", "with", "fulminant", "hepatic", "failure", ".", "BACKGROUND", ":", "To", "review", "evidence-based", "treatment", "options", "in", "patients", "with", "cerebral", "edema", "complicating", "fulminant", "hepatic", "failure", "(", "FHF", ")", "and", "discuss", "the", "potential", "applications", "of", "hypothermia", ".", "METHOD", ":", "Case-based", "observations", "from", "a", "medical", "intensive", "care", "unit", "(", "MICU", ")", "in", "a", "tertiary", "care", "facility", "in", "a", "27-year-old", "female", "with", "FHF", "from", "acetaminophen", "and", "resultant", "cerebral", "edema", ".", "RESULTS", ":", "Our", "patient", "was", "admitted", "to", "the", "MICU", "after", "being", "found", "unresponsive", "with", "presumed", "toxicity", "from", "acetaminophen", "which", "was", "ingested", "over", "a", "2-day", "period", ".", "The", "patient", "had", "depressed", "of", "mental", "status", "lasting", "at", "least", "24", "h", "prior", "to", "admission", ".", "Initial", "evaluation", "confirmed", "FHF", "from", "acetaminophen", "and", "cerebral", "edema", ".", "The", "patient", "was", "treated", "with", "hyperosmolar", "therapy", ",", "hyperventilation", ",", "sedation", ",", "and", "chemical", "paralysis", ".", "Her", "intracranial", "pressure", "remained", "elevated", "despite", "maximal", "medical", "therapy", ".", "We", "then", "initiated", "therapeutic", "hypothermia", "which", "was", "continued", "for", "5", "days", ".", "At", "re-warming", ",", "patient", "had", "resolution", "of", "her", "cerebral", "edema", "and", "intracranial", "hypertension", ".", "At", "discharge", ",", "she", "had", "complete", "recovery", "of", "neurological", "and", "hepatic", "functions", ".", "CONCLUSION", ":", "In", "patients", "with", "FHF", "and", "cerebral", "edema", "from", "acetaminophen", "overdose", ",", "prolonged", "therapeutic", "hypothermia", "could", "potentially", "be", "used", "as", "a", "life", "saving", "therapy", "and", "a", "bridge", "to", "hepatic", "and", "neurological", "recovery", ".", "A", "clinical", "trial", "of", "hypothermia", "in", "patients", "with", "this", "condition", "is", "warranted", "." ]
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20606392
Atypical GH insensitivity syndrome and severe insulin-like growth factor-I deficiency resulting from compound heterozygous mutations of the GH receptor, including a novel frameshift mutation affecting the intracellular domain. BACKGROUND/AIMS: GH insensitivity and IGF deficiency may result from aberrations of the GH receptor (GHR). We describe a 4-year-old child with modest growth failure and normal serum concentrations of GH-binding protein (GHBP), but clinical evidence of GH insensitivity. METHOD: Serum and DNA samples from the proband and his parents were analyzed. RESULTS: The child had a height of -4 SD, elevated serum GH concentrations, abnormally low serum IGF-I and IGFBP-3 concentrations and normal GHBP concentrations. DNA analysis revealed compound heterozygosity for mutations of GHR, including a previously reported R211H mutation and a novel duplication of a nucleotide in exon 9 (899dupC), the latter resulting in a frameshift and a premature stop codon. Treatment with recombinant DNA-derived IGF-I resulted in growth acceleration. CONCLUSION: Mutations affecting the intracellular domain of the GHR can result in GH insensitivity and IGF deficiency, despite normal serum concentrations of GHBP. The presence of clinical and biochemical evidence of GH resistance is sufficient to consider the possibility of aberrations of the GHR, even in the presence of normal serum GHBP concentrations.
[ "Atypical", "GH", "insensitivity", "syndrome", "and", "severe", "insulin-like", "growth", "factor-I", "deficiency", "resulting", "from", "compound", "heterozygous", "mutations", "of", "the", "GH", "receptor", ",", "including", "a", "novel", "frameshift", "mutation", "affecting", "the", "intracellular", "domain", ".", "BACKGROUND/AIMS", ":", "GH", "insensitivity", "and", "IGF", "deficiency", "may", "result", "from", "aberrations", "of", "the", "GH", "receptor", "(", "GHR", ")", ".", "We", "describe", "a", "4-year-old", "child", "with", "modest", "growth", "failure", "and", "normal", "serum", "concentrations", "of", "GH-binding", "protein", "(", "GHBP", ")", ",", "but", "clinical", "evidence", "of", "GH", "insensitivity", ".", "METHOD", ":", "Serum", "and", "DNA", "samples", "from", "the", "proband", "and", "his", "parents", "were", "analyzed", ".", "RESULTS", ":", "The", "child", "had", "a", "height", "of", "-4", "SD", ",", "elevated", "serum", "GH", "concentrations", ",", "abnormally", "low", "serum", "IGF-I", "and", "IGFBP-3", "concentrations", "and", "normal", "GHBP", "concentrations", ".", "DNA", "analysis", "revealed", "compound", "heterozygosity", "for", "mutations", "of", "GHR", ",", "including", "a", "previously", "reported", "R211H", "mutation", "and", "a", "novel", "duplication", "of", "a", "nucleotide", "in", "exon", "9", "(", "899dupC", ")", ",", "the", "latter", "resulting", "in", "a", "frameshift", "and", "a", "premature", "stop", "codon", ".", "Treatment", "with", "recombinant", "DNA-derived", "IGF-I", "resulted", "in", "growth", "acceleration", ".", "CONCLUSION", ":", "Mutations", "affecting", "the", "intracellular", "domain", "of", "the", "GHR", "can", "result", "in", "GH", "insensitivity", "and", "IGF", "deficiency", ",", "despite", "normal", "serum", "concentrations", "of", "GHBP", ".", "The", "presence", "of", "clinical", "and", "biochemical", "evidence", "of", "GH", "resistance", "is", "sufficient", "to", "consider", "the", "possibility", "of", "aberrations", "of", "the", "GHR", ",", "even", "in", "the", "presence", "of", "normal", "serum", "GHBP", "concentrations", "." ]
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20806042
A novel mutation in GJA8 causing congenital cataract-microcornea syndrome in a Chinese pedigree. PURPOSE: To identify the underlying genetic defect in a four-generation family of Chinese origin with autosomal dominant congenital cataract-microcornea syndrome (CCMC). METHODS: All individuals in the study underwent a full clinical examination and the details of history were collected . Genomic DNA extracted from peripheral blood was amplified by polymerase chain reaction (PCR) method and the exons of all candidate genes were sequenced. RESULTS: Direct sequencing of the encoding regions of the candidate genes revealed a heterozygous mutation c.592C-->T in exon 2 of the gap junction protein, alpha 8 (GJA8) gene. This mutation was responsible for the familial disorder through the substitution of a highly conserved arginine to tryptophan at codon 198 (p.R198W). This change co-segregated with all affected members of the family, but was not detected either in the non-carrier relatives or in the 100 normal controls. CONCLUSIONS: This report is the first to relate p.R198W mutation in GJA8 with CCMC. The result expands the mutation spectrum of GJA8 in associated with congenital cataract and microcornea, and implies that this gene has direct involvement with the development of the lens as well as the other anterior segment of the eye.
[ "A", "novel", "mutation", "in", "GJA8", "causing", "congenital", "cataract-microcornea", "syndrome", "in", "a", "Chinese", "pedigree", ".", "PURPOSE", ":", "To", "identify", "the", "underlying", "genetic", "defect", "in", "a", "four-generation", "family", "of", "Chinese", "origin", "with", "autosomal", "dominant", "congenital", "cataract-microcornea", "syndrome", "(", "CCMC", ")", ".", "METHODS", ":", "All", "individuals", "in", "the", "study", "underwent", "a", "full", "clinical", "examination", "and", "the", "details", "of", "history", "were", "collected", ".", "Genomic", "DNA", "extracted", "from", "peripheral", "blood", "was", "amplified", "by", "polymerase", "chain", "reaction", "(", "PCR", ")", "method", "and", "the", "exons", "of", "all", "candidate", "genes", "were", "sequenced", ".", "RESULTS", ":", "Direct", "sequencing", "of", "the", "encoding", "regions", "of", "the", "candidate", "genes", "revealed", "a", "heterozygous", "mutation", "c.592C", "--", ">", "T", "in", "exon", "2", "of", "the", "gap", "junction", "protein", ",", "alpha", "8", "(", "GJA8", ")", "gene", ".", "This", "mutation", "was", "responsible", "for", "the", "familial", "disorder", "through", "the", "substitution", "of", "a", "highly", "conserved", "arginine", "to", "tryptophan", "at", "codon", "198", "(", "p.R198W", ")", ".", "This", "change", "co-segregated", "with", "all", "affected", "members", "of", "the", "family", ",", "but", "was", "not", "detected", "either", "in", "the", "non-carrier", "relatives", "or", "in", "the", "100", "normal", "controls", ".", "CONCLUSIONS", ":", "This", "report", "is", "the", "first", "to", "relate", "p.R198W", "mutation", "in", "GJA8", "with", "CCMC", ".", "The", "result", "expands", "the", "mutation", "spectrum", "of", "GJA8", "in", "associated", "with", "congenital", "cataract", "and", "microcornea", ",", "and", "implies", "that", "this", "gene", "has", "direct", "involvement", "with", "the", "development", "of", "the", "lens", "as", "well", "as", "the", "other", "anterior", "segment", "of", "the", "eye", "." ]
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21163864
The M235T polymorphism of the angiotensinogen gene in South Indian patients of hypertrophic cardiomyopathy. INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is a complex disorder and genetically transmitted cardiac disease with a diverse clinical course. The objective of the present study was to examine the association of the T704C polymorphism of exon 2 of the angiotensinogen (AGT) gene with HCM in a South Indian population from Andhra Pradesh. Subjects and methods. One-hundred and fifty HCM (90 sporadic hypertrophic cardiomyopathy [SHCM] and 60 familial hypertrophic cardiomyopathy [FHCM]) patients and 165 age- and sex-matched normal healthy controls without known hypertension and left ventricular hypertrophy were included in the study. DNA was isolated from peripheral leukocytes and the region of interest in the AGT gene bearing a missense mutation methionine to threonine substitution at codon 235 (M235T) of exon 2, was amplified by polymerase chain reaction (PCR). The PCR products were subjected to restriction digestion with the enzyme SfaNI. RESULTS: Significant differences were detected in genotypic distribution (p = 0.04) as well as the allelic frequency (p = 0.003) between the SHCM patients and controls. The polymorphism did not show any association with FHCM. CONCLUSION: Our results suggest that the T allele of the AGT gene is significantly associated with SHCM in a South Indian population from Andhra Pradesh. However, we did not find significant association of this polymorphism with FHCM.
[ "The", "M235T", "polymorphism", "of", "the", "angiotensinogen", "gene", "in", "South", "Indian", "patients", "of", "hypertrophic", "cardiomyopathy", ".", "INTRODUCTION", ":", "Hypertrophic", "cardiomyopathy", "(", "HCM", ")", "is", "a", "complex", "disorder", "and", "genetically", "transmitted", "cardiac", "disease", "with", "a", "diverse", "clinical", "course", ".", "The", "objective", "of", "the", "present", "study", "was", "to", "examine", "the", "association", "of", "the", "T704C", "polymorphism", "of", "exon", "2", "of", "the", "angiotensinogen", "(", "AGT", ")", "gene", "with", "HCM", "in", "a", "South", "Indian", "population", "from", "Andhra", "Pradesh", ".", "Subjects", "and", "methods", ".", "One-hundred", "and", "fifty", "HCM", "(", "90", "sporadic", "hypertrophic", "cardiomyopathy", "[", "SHCM", "]", "and", "60", "familial", "hypertrophic", "cardiomyopathy", "[", "FHCM", "]", ")", "patients", "and", "165", "age-", "and", "sex-matched", "normal", "healthy", "controls", "without", "known", "hypertension", "and", "left", "ventricular", "hypertrophy", "were", "included", "in", "the", "study", ".", "DNA", "was", "isolated", "from", "peripheral", "leukocytes", "and", "the", "region", "of", "interest", "in", "the", "AGT", "gene", "bearing", "a", "missense", "mutation", "methionine", "to", "threonine", "substitution", "at", "codon", "235", "(", "M235T", ")", "of", "exon", "2", ",", "was", "amplified", "by", "polymerase", "chain", "reaction", "(", "PCR", ")", ".", "The", "PCR", "products", "were", "subjected", "to", "restriction", "digestion", "with", "the", "enzyme", "SfaNI", ".", "RESULTS", ":", "Significant", "differences", "were", "detected", "in", "genotypic", "distribution", "(", "p", "=", "0.04", ")", "as", "well", "as", "the", "allelic", "frequency", "(", "p", "=", "0.003", ")", "between", "the", "SHCM", "patients", "and", "controls", ".", "The", "polymorphism", "did", "not", "show", "any", "association", "with", "FHCM", ".", "CONCLUSION", ":", "Our", "results", "suggest", "that", "the", "T", "allele", "of", "the", "AGT", "gene", "is", "significantly", "associated", "with", "SHCM", "in", "a", "South", "Indian", "population", "from", "Andhra", "Pradesh", ".", "However", ",", "we", "did", "not", "find", "significant", "association", "of", "this", "polymorphism", "with", "FHCM", "." ]
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21682595
XRCC1 Arg399Gln gene polymorphism and the risk of systemic lupus erythematosus in the Polish population. It has been shown that DNA repair is reduced in patients with systemic lupus erythematosus (SLE) and that the X-ray repair cross-complementing (XRCC1) Arg399Gln (rs25487) polymorphism may contribute to DNA repair. We evaluated the frequency of the XRCC1 Arg399Gln substitution in patients with SLE (n=265) and controls (n=360) in a sample of the Polish population. The odds ratio (OR) for SLE patients with the Gln/Gln versus Gln/Arg or Arg/Arg genotypes was 1.553 (95% confidence interval [CI]=0.9573-2.520; p=0.0729). OR for the Gln/Gln or Gln/Arg versus Arg/Arg genotype was 1.551 (95% CI=1.122-2.144, p=0.0077). The OR for the 399 Gln allele in patients with SLE was 1.406 (95% CI=1.111-1.779, p=0.0045). There was also a statistically significant p-value of the (2) test for the trend observed in the XRCC1 Arg399Gln polymorphism (ptrend=0.0048). We also found a significant contribution of the Gln/Gln or Arg/Gln versus Arg/Arg genotype to the presence of either the malar rash or photosensitivity manifestations of SLE OR=2.241 (1.328-3.781, p=0.0023, pcorr=0.0414). Moreover, the meta-analysis of Taiwanese Han Chinese, Brazilian, and Polish populations showed that the Gln/Gln or Gln/Arg genotype and Gln allele were associated with SLE incidence. OR for the Gln/Gln or Gln/Arg versus Arg/Arg genotype was 1.440 (95% CI=1.15-1.80, p=0.0019) and OR for the Gln allele was 1.27 (95% CI=1.08-1.51, p=0.0051). Our studies may confirm that the XRCC1 Arg399Gln polymorphism may increase the risk of incidence of SLE and the occurrence of some SLE manifestations.
[ "XRCC1", "Arg399Gln", "gene", "polymorphism", "and", "the", "risk", "of", "systemic", "lupus", "erythematosus", "in", "the", "Polish", "population", ".", "It", "has", "been", "shown", "that", "DNA", "repair", "is", "reduced", "in", "patients", "with", "systemic", "lupus", "erythematosus", "(", "SLE", ")", "and", "that", "the", "X-ray", "repair", "cross-complementing", "(", "XRCC1", ")", "Arg399Gln", "(", "rs25487", ")", "polymorphism", "may", "contribute", "to", "DNA", "repair", ".", "We", "evaluated", "the", "frequency", "of", "the", "XRCC1", "Arg399Gln", "substitution", "in", "patients", "with", "SLE", "(", "n=265", ")", "and", "controls", "(", "n=360", ")", "in", "a", "sample", "of", "the", "Polish", "population", ".", "The", "odds", "ratio", "(", "OR", ")", "for", "SLE", "patients", "with", "the", "Gln/Gln", "versus", "Gln/Arg", "or", "Arg/Arg", "genotypes", "was", "1.553", "(", "95", "%", "confidence", "interval", "[", "CI", "]", "=0.9573-2.520", ";", "p=0.0729", ")", ".", "OR", "for", "the", "Gln/Gln", "or", "Gln/Arg", "versus", "Arg/Arg", "genotype", "was", "1.551", "(", "95", "%", "CI=1.122-2.144", ",", "p=0.0077", ")", ".", "The", "OR", "for", "the", "399", "Gln", "allele", "in", "patients", "with", "SLE", "was", "1.406", "(", "95", "%", "CI=1.111-1.779", ",", "p=0.0045", ")", ".", "There", "was", "also", "a", "statistically", "significant", "p-value", "of", "the", "(", "2", ")", "test", "for", "the", "trend", "observed", "in", "the", "XRCC1", "Arg399Gln", "polymorphism", "(", "ptrend=0.0048", ")", ".", "We", "also", "found", "a", "significant", "contribution", "of", "the", "Gln/Gln", "or", "Arg/Gln", "versus", "Arg/Arg", "genotype", "to", "the", "presence", "of", "either", "the", "malar", "rash", "or", "photosensitivity", "manifestations", "of", "SLE", "OR=2.241", "(", "1.328-3.781", ",", "p=0.0023", ",", "pcorr=0.0414", ")", ".", "Moreover", ",", "the", "meta-analysis", "of", "Taiwanese", "Han", "Chinese", ",", "Brazilian", ",", "and", "Polish", "populations", "showed", "that", "the", "Gln/Gln", "or", "Gln/Arg", "genotype", "and", "Gln", "allele", "were", "associated", "with", "SLE", "incidence", ".", "OR", "for", "the", "Gln/Gln", "or", "Gln/Arg", "versus", "Arg/Arg", "genotype", "was", "1.440", "(", "95", "%", "CI=1.15-1.80", ",", "p=0.0019", ")", "and", "OR", "for", "the", "Gln", "allele", "was", "1.27", "(", "95", "%", "CI=1.08-1.51", ",", "p=0.0051", ")", ".", "Our", "studies", "may", "confirm", "that", "the", "XRCC1", "Arg399Gln", "polymorphism", "may", "increase", "the", "risk", "of", "incidence", "of", "SLE", "and", "the", "occurrence", "of", "some", "SLE", "manifestations", "." ]
[ "1", "5", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "2", "2", "2", "0", "2", "0", "0", "0", "0", "1", "1", "1", "0", "1", "0", "5", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "5", "0", "0", "4", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "0", "0", "4", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "5", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "2", "0", "0" ]
24126708
Association of common genetic variants of HOMER1 gene with levodopa adverse effects in Parkinson's disease patients. Levodopa is the most effective symptomatic therapy for Parkinson's disease, but its chronic use could lead to chronic adverse outcomes, such as motor fluctuations, dyskinesia and visual hallucinations. HOMER1 is a protein with pivotal function in glutamate transmission, which has been related to the pathogenesis of these complications. This study investigates whether polymorphisms in the HOMER1 gene promoter region are associated with the occurrence of the chronic complications of levodopa therapy. A total of 205 patients with idiopathic Parkinson's disease were investigated. Patients were genotyped for rs4704559, rs10942891 and rs4704560 by allelic discrimination with Taqman assays. The rs4704559 G allele was associated with a lower prevalence of dyskinesia (prevalence ratio (PR)=0.615, 95% confidence interval (CI) 0.426-0.887, P=0.009) and visual hallucinations (PR=0.515, 95% CI 0.295-0.899, P=0.020). Our data suggest that HOMER1 rs4704559 G allele has a protective role for the development of levodopa adverse effects.
[ "Association", "of", "common", "genetic", "variants", "of", "HOMER1", "gene", "with", "levodopa", "adverse", "effects", "in", "Parkinson", "'s", "disease", "patients", ".", "Levodopa", "is", "the", "most", "effective", "symptomatic", "therapy", "for", "Parkinson", "'s", "disease", ",", "but", "its", "chronic", "use", "could", "lead", "to", "chronic", "adverse", "outcomes", ",", "such", "as", "motor", "fluctuations", ",", "dyskinesia", "and", "visual", "hallucinations", ".", "HOMER1", "is", "a", "protein", "with", "pivotal", "function", "in", "glutamate", "transmission", ",", "which", "has", "been", "related", "to", "the", "pathogenesis", "of", "these", "complications", ".", "This", "study", "investigates", "whether", "polymorphisms", "in", "the", "HOMER1", "gene", "promoter", "region", "are", "associated", "with", "the", "occurrence", "of", "the", "chronic", "complications", "of", "levodopa", "therapy", ".", "A", "total", "of", "205", "patients", "with", "idiopathic", "Parkinson", "'s", "disease", "were", "investigated", ".", "Patients", "were", "genotyped", "for", "rs4704559", ",", "rs10942891", "and", "rs4704560", "by", "allelic", "discrimination", "with", "Taqman", "assays", ".", "The", "rs4704559", "G", "allele", "was", "associated", "with", "a", "lower", "prevalence", "of", "dyskinesia", "(", "prevalence", "ratio", "(", "PR", ")", "=0.615", ",", "95", "%", "confidence", "interval", "(", "CI", ")", "0.426-0.887", ",", "P=0.009", ")", "and", "visual", "hallucinations", "(", "PR=0.515", ",", "95", "%", "CI", "0.295-0.899", ",", "P=0.020", ")", ".", "Our", "data", "suggest", "that", "HOMER1", "rs4704559", "G", "allele", "has", "a", "protective", "role", "for", "the", "development", "of", "levodopa", "adverse", "effects", "." ]
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25983002
Inhibition of LDHA suppresses tumor progression in prostate cancer. A key hallmark of cancer cells is their altered metabolism, known as Warburg effect. Lactate dehydrogenase A (LDHA) executes the final step of aerobic glycolysis and has been reported to be involved in the tumor progression. However, the function of LDHA in prostate cancer has not been studied. In current study, we observed overexpression of LDHA in the clinical prostate cancer samples compared with benign prostate hyperplasia tissues as demonstrated by immunohistochemistry and real-time qPCR. Attenuated expression of LDHA by siRNA or inhibition of LDHA activities by FX11 inhibited cell proliferation, migration, invasion, and promoted cell apoptosis of PC-3 and DU145 cells. Mechanistically, decreased Warburg effect as demonstrated by reduced glucose consumption and lactate secretion and reduced expression of MMP-9, PLAU, and cathepsin B were found after LDHA knockdown or FX11 treatment in PC-3 and DU145 cells. Taken together, our study revealed the oncogenic role of LDHA in prostate cancer and suggested that LDHA might be a potential therapeutic target.
[ "Inhibition", "of", "LDHA", "suppresses", "tumor", "progression", "in", "prostate", "cancer", ".", "A", "key", "hallmark", "of", "cancer", "cells", "is", "their", "altered", "metabolism", ",", "known", "as", "Warburg", "effect", ".", "Lactate", "dehydrogenase", "A", "(", "LDHA", ")", "executes", "the", "final", "step", "of", "aerobic", "glycolysis", "and", "has", "been", "reported", "to", "be", "involved", "in", "the", "tumor", "progression", ".", "However", ",", "the", "function", "of", "LDHA", "in", "prostate", "cancer", "has", "not", "been", "studied", ".", "In", "current", "study", ",", "we", "observed", "overexpression", "of", "LDHA", "in", "the", "clinical", "prostate", "cancer", "samples", "compared", "with", "benign", "prostate", "hyperplasia", "tissues", "as", "demonstrated", "by", "immunohistochemistry", "and", "real-time", "qPCR", ".", "Attenuated", "expression", "of", "LDHA", "by", "siRNA", "or", "inhibition", "of", "LDHA", "activities", "by", "FX11", "inhibited", "cell", "proliferation", ",", "migration", ",", "invasion", ",", "and", "promoted", "cell", "apoptosis", "of", "PC-3", "and", "DU145", "cells", ".", "Mechanistically", ",", "decreased", "Warburg", "effect", "as", "demonstrated", "by", "reduced", "glucose", "consumption", "and", "lactate", "secretion", "and", "reduced", "expression", "of", "MMP-9", ",", "PLAU", ",", "and", "cathepsin", "B", "were", "found", "after", "LDHA", "knockdown", "or", "FX11", "treatment", "in", "PC-3", "and", "DU145", "cells", ".", "Taken", "together", ",", "our", "study", "revealed", "the", "oncogenic", "role", "of", "LDHA", "in", "prostate", "cancer", "and", "suggested", "that", "LDHA", "might", "be", "a", "potential", "therapeutic", "target", "." ]
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27640183
Erythropoietin does not activate erythropoietin receptor signaling or lipolytic pathways in human subcutaneous white adipose tissue in vivo. BACKGROUND: Erythropoietin (Epo) exerts direct effects on white adipose tissue (WAT) in mice in addition to its erythropoietic effects, and in humans Epo increases resting energy expenditure and affect serum lipid levels, but direct effects of Epo in human WAT have not been documented. We therefore investigated the effects of acute and prolonged Epo exposure on human WAT in vivo. METHOD: Data were obtained from two clinical trials: 1) acute Epo exposure (rHuEpo, 400 IU/kg) followed by WAT biopsies after 1 h and 2) 10 weeks treatment with the erythropoiesis-stimulating agent (ESA) Darbepoietin-alpha. Biopsies were analyzed by PCR for Epo receptor (Epo-R) mRNA. A new and highly specific antibody (A82, Amgen) was used to evaluate the presence of Epo-R by western blot analysis in addition to Epo-R signaling proteins (Akt, STAT5, p70s6k, LYN, and p38MAPK), activation of lipolytic pathways (ATGL, HSL, CGI-58, G0S2, Perilipin, Cidea, Cidec, AMPK, and ACC), and mitochondrial biogenesis (VDAC, HSP90, PDH, and SDHA). RESULTS: No evidence of in vivo activation of the Epo-R in WAT could be documented despite detectable levels of Epo-R mRNA. CONCLUSION: Thus, in contradiction to animal studies, Epo treatment within a physiological relevant range in humans does not exert direct effects in a subcutaneous WAT.
[ "Erythropoietin", "does", "not", "activate", "erythropoietin", "receptor", "signaling", "or", "lipolytic", "pathways", "in", "human", "subcutaneous", "white", "adipose", "tissue", "in", "vivo", ".", "BACKGROUND", ":", "Erythropoietin", "(", "Epo", ")", "exerts", "direct", "effects", "on", "white", "adipose", "tissue", "(", "WAT", ")", "in", "mice", "in", "addition", "to", "its", "erythropoietic", "effects", ",", "and", "in", "humans", "Epo", "increases", "resting", "energy", "expenditure", "and", "affect", "serum", "lipid", "levels", ",", "but", "direct", "effects", "of", "Epo", "in", "human", "WAT", "have", "not", "been", "documented", ".", "We", "therefore", "investigated", "the", "effects", "of", "acute", "and", "prolonged", "Epo", "exposure", "on", "human", "WAT", "in", "vivo", ".", "METHOD", ":", "Data", "were", "obtained", "from", "two", "clinical", "trials", ":", "1", ")", "acute", "Epo", "exposure", "(", "rHuEpo", ",", "400", "IU/kg", ")", "followed", "by", "WAT", "biopsies", "after", "1", "h", "and", "2", ")", "10", "weeks", "treatment", "with", "the", "erythropoiesis-stimulating", "agent", "(", "ESA", ")", "Darbepoietin-alpha", ".", "Biopsies", "were", "analyzed", "by", "PCR", "for", "Epo", "receptor", "(", "Epo-R", ")", "mRNA", ".", "A", "new", "and", "highly", "specific", "antibody", "(", "A82", ",", "Amgen", ")", "was", "used", "to", "evaluate", "the", "presence", "of", "Epo-R", "by", "western", "blot", "analysis", "in", "addition", "to", "Epo-R", "signaling", "proteins", "(", "Akt", ",", "STAT5", ",", "p70s6k", ",", "LYN", ",", "and", "p38MAPK", ")", ",", "activation", "of", "lipolytic", "pathways", "(", "ATGL", ",", "HSL", ",", "CGI-58", ",", "G0S2", ",", "Perilipin", ",", "Cidea", ",", "Cidec", ",", "AMPK", ",", "and", "ACC", ")", ",", "and", "mitochondrial", "biogenesis", "(", "VDAC", ",", "HSP90", ",", "PDH", ",", "and", "SDHA", ")", ".", "RESULTS", ":", "No", "evidence", "of", "in", "vivo", "activation", "of", "the", "Epo-R", "in", "WAT", "could", "be", "documented", "despite", "detectable", "levels", "of", "Epo-R", "mRNA", ".", "CONCLUSION", ":", "Thus", ",", "in", "contradiction", "to", "animal", "studies", ",", "Epo", "treatment", "within", "a", "physiological", "relevant", "range", "in", "humans", "does", "not", "exert", "direct", "effects", "in", "a", "subcutaneous", "WAT", "." ]
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28411266
Genetic Variation at the Sulfonylurea Receptor, Type 2 Diabetes, and Coronary Heart Disease. Despite widespread clinical use in the treatment of type 2 diabetes, the impact of sulfonylurea therapy on cardiovascular outcomes remains uncertain. Studies of naturally occurring genetic variation can be used to anticipate the expected clinical consequences of a pharmacological therapy. A common missense variant in the gene encoding a component of the sulfonylurea receptor (ABCC8 p.A1369S) promotes closure of the target channel of sulfonylurea therapy and is associated with increased insulin secretion, thus mimicking the effects of sulfonylurea therapy. Using individual-level data from 120,286 participants in the UK Biobank and summary association results from four large-scale genome-wide association studies, we examined the impact of this variant on cardiometabolic traits, type 2 diabetes, and coronary heart disease. The p.A1369S variant was associated with a significantly lower risk of type 2 diabetes (odds ratio [OR] 0.93; 95% CI 0.91, 0.95; P = 1.2 x 10(-11)). The variant was associated with increased BMI (+0.062 kg/m(2); 95% CI 0.037, 0.086; P = 8.1 x 10(-7)) but lower waist-to-hip ratio adjusted for BMI, a marker of abdominal fat distribution. Furthermore, p.A1369S was associated with a reduced risk of coronary heart disease (OR 0.98; 95% CI 0.96, 0.99; P = 5.9 x 10(-4)). These results suggest that, despite a known association with increased weight, long-term sulfonylurea therapy may reduce the risk of coronary heart disease.
[ "Genetic", "Variation", "at", "the", "Sulfonylurea", "Receptor", ",", "Type", "2", "Diabetes", ",", "and", "Coronary", "Heart", "Disease", ".", "Despite", "widespread", "clinical", "use", "in", "the", "treatment", "of", "type", "2", "diabetes", ",", "the", "impact", "of", "sulfonylurea", "therapy", "on", "cardiovascular", "outcomes", "remains", "uncertain", ".", "Studies", "of", "naturally", "occurring", "genetic", "variation", "can", "be", "used", "to", "anticipate", "the", "expected", "clinical", "consequences", "of", "a", "pharmacological", "therapy", ".", "A", "common", "missense", "variant", "in", "the", "gene", "encoding", "a", "component", "of", "the", "sulfonylurea", "receptor", "(", "ABCC8", "p.A1369S", ")", "promotes", "closure", "of", "the", "target", "channel", "of", "sulfonylurea", "therapy", "and", "is", "associated", "with", "increased", "insulin", "secretion", ",", "thus", "mimicking", "the", "effects", "of", "sulfonylurea", "therapy", ".", "Using", "individual-level", "data", "from", "120,286", "participants", "in", "the", "UK", "Biobank", "and", "summary", "association", "results", "from", "four", "large-scale", "genome-wide", "association", "studies", ",", "we", "examined", "the", "impact", "of", "this", "variant", "on", "cardiometabolic", "traits", ",", "type", "2", "diabetes", ",", "and", "coronary", "heart", "disease", ".", "The", "p.A1369S", "variant", "was", "associated", "with", "a", "significantly", "lower", "risk", "of", "type", "2", "diabetes", "(", "odds", "ratio", "[", "OR", "]", "0.93", ";", "95", "%", "CI", "0.91", ",", "0.95", ";", "P", "=", "1.2", "x", "10", "(", "-11", ")", ")", ".", "The", "variant", "was", "associated", "with", "increased", "BMI", "(", "+0.062", "kg/m", "(", "2", ")", ";", "95", "%", "CI", "0.037", ",", "0.086", ";", "P", "=", "8.1", "x", "10", "(", "-7", ")", ")", "but", "lower", "waist-to-hip", "ratio", "adjusted", "for", "BMI", ",", "a", "marker", "of", "abdominal", "fat", "distribution", ".", "Furthermore", ",", "p.A1369S", "was", "associated", "with", "a", "reduced", "risk", "of", "coronary", "heart", "disease", "(", "OR", "0.98", ";", "95", "%", "CI", "0.96", ",", "0.99", ";", "P", "=", "5.9", "x", "10", "(", "-4", ")", ")", ".", "These", "results", "suggest", "that", ",", "despite", "a", "known", "association", "with", "increased", "weight", ",", "long-term", "sulfonylurea", "therapy", "may", "reduce", "the", "risk", "of", "coronary", "heart", "disease", "." ]
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7468724
Cardiovascular complications associated with terbutaline treatment for preterm labor. Severe cardiovascular complications occurred in eight of 160 patients treated with terbutaline for preterm labor. Associated corticosteroid therapy and twin gestations appear to be predisposing factors. Potential mechanisms of the pathophysiology are briefly discussed.
[ "Cardiovascular", "complications", "associated", "with", "terbutaline", "treatment", "for", "preterm", "labor", ".", "Severe", "cardiovascular", "complications", "occurred", "in", "eight", "of", "160", "patients", "treated", "with", "terbutaline", "for", "preterm", "labor", ".", "Associated", "corticosteroid", "therapy", "and", "twin", "gestations", "appear", "to", "be", "predisposing", "factors", ".", "Potential", "mechanisms", "of", "the", "pathophysiology", "are", "briefly", "discussed", "." ]
[ "2", "2", "0", "0", "3", "0", "0", "2", "2", "0", "0", "2", "2", "0", "0", "0", "0", "0", "4", "0", "0", "3", "0", "2", "2", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]
7668252
Cloning of human very-long-chain acyl-coenzyme A dehydrogenase and molecular characterization of its deficiency in two patients. Two overlapping cDNA clones (1, 991 bp and 736 bp, respectively) encoding the precursor of human mitochondrial very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) were cloned and sequenced. The cDNA inserts of these clones together encompass a region of 2, 177 bases, encoding the entire protein of 655 amino acids, including a 40-amino acid leader peptide and a 615-amino acid mature polypeptide. PCR-amplified VLCAD cDNAs were sequenced in cultured fibroblasts from two VLCAD-deficient patients. In both patients, a 105-bp deletion encompassing bases 1078-1182 in VLCAD cDNA was identified. The deletion seems to occur due to exon skipping during processing of VLCAD pre-mRNA. This is the first demonstration of a mutation causing VLCAD deficiency. Quantitative cDNA expression of normal human VLCAD was performed in the patients fibroblasts, using vaccinia viral system, which demonstrated that the deficiency of the normal VLCAD protein causes impaired long-chain fatty acid beta-oxidation activity in the patients fibroblasts. In patient fibroblasts, raising VLCAD activity to approximately 20% of normal control fibroblast activity raised palmitic acid beta-oxidation flux to the level found in control fibroblasts, which may offer important information for the rational design of future somatic gene therapy for VLCAD deficiency..
[ "Cloning", "of", "human", "very-long-chain", "acyl-coenzyme", "A", "dehydrogenase", "and", "molecular", "characterization", "of", "its", "deficiency", "in", "two", "patients", ".", "Two", "overlapping", "cDNA", "clones", "(", "1", ",", "991", "bp", "and", "736", "bp", ",", "respectively", ")", "encoding", "the", "precursor", "of", "human", "mitochondrial", "very-long-chain", "acyl-coenzyme", "A", "dehydrogenase", "(", "VLCAD", ")", "were", "cloned", "and", "sequenced", ".", "The", "cDNA", "inserts", "of", "these", "clones", "together", "encompass", "a", "region", "of", "2", ",", "177", "bases", ",", "encoding", "the", "entire", "protein", "of", "655", "amino", "acids", ",", "including", "a", "40-amino", "acid", "leader", "peptide", "and", "a", "615-amino", "acid", "mature", "polypeptide", ".", "PCR-amplified", "VLCAD", "cDNAs", "were", "sequenced", "in", "cultured", "fibroblasts", "from", "two", "VLCAD-deficient", "patients", ".", "In", "both", "patients", ",", "a", "105-bp", "deletion", "encompassing", "bases", "1078-1182", "in", "VLCAD", "cDNA", "was", "identified", ".", "The", "deletion", "seems", "to", "occur", "due", "to", "exon", "skipping", "during", "processing", "of", "VLCAD", "pre-mRNA", ".", "This", "is", "the", "first", "demonstration", "of", "a", "mutation", "causing", "VLCAD", "deficiency", ".", "Quantitative", "cDNA", "expression", "of", "normal", "human", "VLCAD", "was", "performed", "in", "the", "patients", "fibroblasts", ",", "using", "vaccinia", "viral", "system", ",", "which", "demonstrated", "that", "the", "deficiency", "of", "the", "normal", "VLCAD", "protein", "causes", "impaired", "long-chain", "fatty", "acid", "beta-oxidation", "activity", "in", "the", "patients", "fibroblasts", ".", "In", "patient", "fibroblasts", ",", "raising", "VLCAD", "activity", "to", "approximately", "20", "%", "of", "normal", "control", "fibroblast", "activity", "raised", "palmitic", "acid", "beta-oxidation", "flux", "to", "the", "level", "found", "in", "control", "fibroblasts", ",", "which", "may", "offer", "important", "information", "for", "the", "rational", "design", "of", "future", "somatic", "gene", "therapy", "for", "VLCAD", "deficiency", ".." ]
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8002973
Adrenoleukodystrophy gene encodes an 80 kDa membrane protein. An antibody against the synthetic C-terminal peptides deduced from the cDNA of the gene responsible for X-linked adrenoleukodystrophy (ALD) was produced to characterize the product of the ALD gene. The antibody reacted with the 80 kDa band protein in control fibroblasts, while no bands were detected in the fibroblasts from a patient with ALD (# 163), in which mRNA of the ALD gene was undetectable based on Northern blot analysis. The 293T cells transfected with the full-coding cDNA inserted in the expression vector produced a new 80 kDa protein, as detected by Western blot. In an immunocytological study, the staining was in a punctate pattern, in the normal fibroblasts. However, there was no punctate staining in the # 163 cells. These data thus indicate that the ALD gene encodes an 80 kDa membrane protein..
[ "Adrenoleukodystrophy", "gene", "encodes", "an", "80", "kDa", "membrane", "protein", ".", "An", "antibody", "against", "the", "synthetic", "C-terminal", "peptides", "deduced", "from", "the", "cDNA", "of", "the", "gene", "responsible", "for", "X-linked", "adrenoleukodystrophy", "(", "ALD", ")", "was", "produced", "to", "characterize", "the", "product", "of", "the", "ALD", "gene", ".", "The", "antibody", "reacted", "with", "the", "80", "kDa", "band", "protein", "in", "control", "fibroblasts", ",", "while", "no", "bands", "were", "detected", "in", "the", "fibroblasts", "from", "a", "patient", "with", "ALD", "(", "#", "163", ")", ",", "in", "which", "mRNA", "of", "the", "ALD", "gene", "was", "undetectable", "based", "on", "Northern", "blot", "analysis", ".", "The", "293T", "cells", "transfected", "with", "the", "full-coding", "cDNA", "inserted", "in", "the", "expression", "vector", "produced", "a", "new", "80", "kDa", "protein", ",", "as", "detected", "by", "Western", "blot", ".", "In", "an", "immunocytological", "study", ",", "the", "staining", "was", "in", "a", "punctate", "pattern", ",", "in", "the", "normal", "fibroblasts", ".", "However", ",", "there", "was", "no", "punctate", "staining", "in", "the", "#", "163", "cells", ".", "These", "data", "thus", "indicate", "that", "the", "ALD", "gene", "encodes", "an", "80", "kDa", "membrane", "protein", ".." ]
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8755918
Mutations associated with variant phenotypes in ataxia-telangiectasia. We have identified 14 families with ataxia-telangiectasia (A-T) in which mutation of the ATM gene is associated with a less severe clinical and cellular phenotype (approximately 10% -15% of A-T families identified in the United Kingdom). In 10 of these families, all the homozygotes have a 137-bp insertion in their cDNA caused by a point mutation in a sequence resembling a splice-donor site. The second A-T allele has a different mutation in each patient. We show that the less severe phenotype in these patients is caused by some degree of normal splicing, which occurs as an alternative product from the insertion-containing allele. The level of the 137-bp PCR product containing the insertion was lowest in two patients who showed a later onset of cerebellar ataxia. A further four families who do not have this insertion have been identified. Mutations detected in two of four of these are missense mutations, normally rare in A-T patients. The demonstration of mutations giving rise to a slightly milder phenotype in A-T raises the interesting question of what range of phenotypes might occur in individuals in whom both mutations are milder. One possibility might be that individuals who are compound heterozygotes for ATM mutations are more common than we realize..
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9746003
Inappropriate use of carbamazepine and vigabatrin in typical absence seizures. Carbamazepine and vigabatrin are contraindicated in typical absence seizures. Of 18 consecutive referrals of children with resistant typical absences only, eight were erroneously treated with carbamazepine either as monotherapy or as an add-on. Vigabatrin was also used in the treatment of two children. Frequency of absences increased in four children treated with carbamazepine and two of these developed myoclonic jerks, which resolved on withdrawal of carbamazepine. Absences were aggravated in both cases where vigabatrin was added on to concurrent treatment. Optimal control of the absences was achieved with sodium valproate, lamotrigine, or ethosuximide alone or in combination.
[ "Inappropriate", "use", "of", "carbamazepine", "and", "vigabatrin", "in", "typical", "absence", "seizures", ".", "Carbamazepine", "and", "vigabatrin", "are", "contraindicated", "in", "typical", "absence", "seizures", ".", "Of", "18", "consecutive", "referrals", "of", "children", "with", "resistant", "typical", "absences", "only", ",", "eight", "were", "erroneously", "treated", "with", "carbamazepine", "either", "as", "monotherapy", "or", "as", "an", "add-on", ".", "Vigabatrin", "was", "also", "used", "in", "the", "treatment", "of", "two", "children", ".", "Frequency", "of", "absences", "increased", "in", "four", "children", "treated", "with", "carbamazepine", "and", "two", "of", "these", "developed", "myoclonic", "jerks", ",", "which", "resolved", "on", "withdrawal", "of", "carbamazepine", ".", "Absences", "were", "aggravated", "in", "both", "cases", "where", "vigabatrin", "was", "added", "on", "to", "concurrent", "treatment", ".", "Optimal", "control", "of", "the", "absences", "was", "achieved", "with", "sodium", "valproate", ",", "lamotrigine", ",", "or", "ethosuximide", "alone", "or", "in", "combination", "." ]
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15609295
Compound heterozygosity for a novel nine-nucleotide deletion and the Asn45Ser missense mutation in the glycoprotein IX gene in a patient with Bernard-Soulier syndrome. Bernard-Soulier syndrome (BSS) is a rare inherited bleeding disorder due to quantitative or qualitative abnormalities in the platelet glycoprotein (GP) Ib/IX/V complex, the major von Willebrand factor receptor. The complex comprises four subunits, each encoded by a separate gene. Several mutations have been described for each of the subunits, except for GPV, as a cause of BSS. We describe here the genetic basis of the disorder in a child with BSS. Flow-cytometric analysis of the patient's platelets showed a markedly reduced surface expression of all three glycoproteins of the GPIb/IX/V complex. DNA sequencing analysis showed the patient to be a compound heterozygote for two mutations in the GPIX gene, a novel nine-nucleotide deletion starting at position 1952 of the gene that changes asparagine 86 for alanine and eliminates amino acids 87, 88, and 89 (arginine, threonine, and proline) and a previously reported point mutation that changes the codon asparagine (AAC) for serine (AGC) at residue 45. Her mother was heterozygous for the Asn45Ser mutation, and her father, for the nine-nucleotide deletion. Our findings suggest that the additive effects of both mutations in the GPIX gene are responsible for the BSS phenotype of the patient.
[ "Compound", "heterozygosity", "for", "a", "novel", "nine-nucleotide", "deletion", "and", "the", "Asn45Ser", "missense", "mutation", "in", "the", "glycoprotein", "IX", "gene", "in", "a", "patient", "with", "Bernard-Soulier", "syndrome", ".", "Bernard-Soulier", "syndrome", "(", "BSS", ")", "is", "a", "rare", "inherited", "bleeding", "disorder", "due", "to", "quantitative", "or", "qualitative", "abnormalities", "in", "the", "platelet", "glycoprotein", "(", "GP", ")", "Ib/IX/V", "complex", ",", "the", "major", "von", "Willebrand", "factor", "receptor", ".", "The", "complex", "comprises", "four", "subunits", ",", "each", "encoded", "by", "a", "separate", "gene", ".", "Several", "mutations", "have", "been", "described", "for", "each", "of", "the", "subunits", ",", "except", "for", "GPV", ",", "as", "a", "cause", "of", "BSS", ".", "We", "describe", "here", "the", "genetic", "basis", "of", "the", "disorder", "in", "a", "child", "with", "BSS", ".", "Flow-cytometric", "analysis", "of", "the", "patient", "'s", "platelets", "showed", "a", "markedly", "reduced", "surface", "expression", "of", "all", "three", "glycoproteins", "of", "the", "GPIb/IX/V", "complex", ".", "DNA", "sequencing", "analysis", "showed", "the", "patient", "to", "be", "a", "compound", "heterozygote", "for", "two", "mutations", "in", "the", "GPIX", "gene", ",", "a", "novel", "nine-nucleotide", "deletion", "starting", "at", "position", "1952", "of", "the", "gene", "that", "changes", "asparagine", "86", "for", "alanine", "and", "eliminates", "amino", "acids", "87", ",", "88", ",", "and", "89", "(", "arginine", ",", "threonine", ",", "and", "proline", ")", "and", "a", "previously", "reported", "point", "mutation", "that", "changes", "the", "codon", "asparagine", "(", "AAC", ")", "for", "serine", "(", "AGC", ")", "at", "residue", "45", ".", "Her", "mother", "was", "heterozygous", "for", "the", "Asn45Ser", "mutation", ",", "and", "her", "father", ",", "for", "the", "nine-nucleotide", "deletion", ".", "Our", "findings", "suggest", "that", "the", "additive", "effects", "of", "both", "mutations", "in", "the", "GPIX", "gene", "are", "responsible", "for", "the", "BSS", "phenotype", "of", "the", "patient", "." ]
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16288197
Genetic homogeneity for inherited congenital microcoria loci in an Asian Indian pedigree. PURPOSE: Congenital microcoria is a rare autosomal dominant developmental disorder of the iris associated with myopia and juvenile open angle glaucoma. Linkage to the chromosomal locus 13q31-q32 has previously been reported in a large French family. In the current study, a three generation Asian Indian family with 15 congenital microcoria (pupils with a diameter <2 mm) affected members was studied for linkage to candidate microsatellite markers at the 13q31-q32 locus. METHODS: Twenty-four members of the family were clinically examined and genomic DNA was extracted. Microsatellite markers at 13q31-q32 were PCR amplified and run on an ABI Prism 310 genetic analyzer and genotyped with the GeneScan analysis. Two point and multipoint linkage analyses were performed using the MLINK and SUPERLINK programs. RESULTS: Peak two point LOD scores of 3.5, 4.7, and 5.3 were found co-incident with consecutive markers D13S154, DCT, and D13S1280. Multipoint analysis revealed a 4 cM region encompassing D13S1300 to D13S1280 where the LOD remains just over 6.0 Thus we confirm localization of the congenital microcoria locus to chromosomal locus 13q31-q32. In addition, eight individuals who had both microcoria and glaucoma were screened for glaucoma genes: myocilin (MYOC), optineurin (OPTN) and CYP1B1. Using direct sequencing a point mutation (144 G>A) resulting in a Q48H substitution in exon 1 of the MYOC gene was observed in five of the eight glaucoma patients, but not in unaffected family members and 100 unrelated controls. CONCLUSIONS: We have confirmed the localization of the congenital microcoria locus (MCOR) to 13q31-q32 in a large Asian Indian family and conclude that current information suggests this is a single locus disorder and genetically homogeneous. When combined with the initial linkage paper our haplotype and linkage data map the MCOR locus to a 6-7 cM region between D13S265 and D13S1280. The DCT locus, a member of the tyrosinase family involved in pigmentation, maps within this region. Data presented here supports the hypothesis that congenital microcoria is a potential risk factor for glaucoma, although this observation is complicated by the partial segregation of MYOC Q48H (1q24.3-q25.2), a mutation known to be associated with glaucoma in India. Fine mapping and candidate gene analysis continues with the hope that characterizing the micocoria gene will lead to a better understanding of microcoria and glaucoma causation. The relationship between microcoria, glaucoma, and the MYOC Q48H mutation in this family is discussed.
[ "Genetic", "homogeneity", "for", "inherited", "congenital", "microcoria", "loci", "in", "an", "Asian", "Indian", "pedigree", ".", "PURPOSE", ":", "Congenital", "microcoria", "is", "a", "rare", "autosomal", "dominant", "developmental", "disorder", "of", "the", "iris", "associated", "with", "myopia", "and", "juvenile", "open", "angle", "glaucoma", ".", "Linkage", "to", "the", "chromosomal", "locus", "13q31-q32", "has", "previously", "been", "reported", "in", "a", "large", "French", "family", ".", "In", "the", "current", "study", ",", "a", "three", "generation", "Asian", "Indian", "family", "with", "15", "congenital", "microcoria", "(", "pupils", "with", "a", "diameter", "<", "2", "mm", ")", "affected", "members", "was", "studied", "for", "linkage", "to", "candidate", "microsatellite", "markers", "at", "the", "13q31-q32", "locus", ".", "METHODS", ":", "Twenty-four", "members", "of", "the", "family", "were", "clinically", "examined", "and", "genomic", "DNA", "was", "extracted", ".", "Microsatellite", "markers", "at", "13q31-q32", "were", "PCR", "amplified", "and", "run", "on", "an", "ABI", "Prism", "310", "genetic", "analyzer", "and", "genotyped", "with", "the", "GeneScan", "analysis", ".", "Two", "point", "and", "multipoint", "linkage", "analyses", "were", "performed", "using", "the", "MLINK", "and", "SUPERLINK", "programs", ".", "RESULTS", ":", "Peak", "two", "point", "LOD", "scores", "of", "3.5", ",", "4.7", ",", "and", "5.3", "were", "found", "co-incident", "with", "consecutive", "markers", "D13S154", ",", "DCT", ",", "and", "D13S1280", ".", "Multipoint", "analysis", "revealed", "a", "4", "cM", "region", "encompassing", "D13S1300", "to", "D13S1280", "where", "the", "LOD", "remains", "just", "over", "6.0", "Thus", "we", "confirm", "localization", "of", "the", "congenital", "microcoria", "locus", "to", "chromosomal", "locus", "13q31-q32", ".", "In", "addition", ",", "eight", "individuals", "who", "had", "both", "microcoria", "and", "glaucoma", "were", "screened", "for", "glaucoma", "genes", ":", "myocilin", "(", "MYOC", ")", ",", "optineurin", "(", "OPTN", ")", "and", "CYP1B1", ".", "Using", "direct", "sequencing", "a", "point", "mutation", "(", "144", "G", ">", "A", ")", "resulting", "in", "a", "Q48H", "substitution", "in", "exon", "1", "of", "the", "MYOC", "gene", "was", "observed", "in", "five", "of", "the", "eight", "glaucoma", "patients", ",", "but", "not", "in", "unaffected", "family", "members", "and", "100", "unrelated", "controls", ".", "CONCLUSIONS", ":", "We", "have", "confirmed", "the", "localization", "of", "the", "congenital", "microcoria", "locus", "(", "MCOR", ")", "to", "13q31-q32", "in", "a", "large", "Asian", "Indian", "family", "and", "conclude", "that", "current", "information", "suggests", "this", "is", "a", "single", "locus", "disorder", "and", "genetically", "homogeneous", ".", "When", "combined", "with", "the", "initial", "linkage", "paper", "our", "haplotype", "and", "linkage", "data", "map", "the", "MCOR", "locus", "to", "a", "6-7", "cM", "region", "between", "D13S265", "and", "D13S1280", ".", "The", "DCT", "locus", ",", "a", "member", "of", "the", "tyrosinase", "family", "involved", "in", "pigmentation", ",", "maps", "within", "this", "region", ".", "Data", "presented", "here", "supports", "the", "hypothesis", "that", "congenital", "microcoria", "is", "a", "potential", "risk", "factor", "for", "glaucoma", ",", "although", "this", "observation", "is", "complicated", "by", "the", "partial", "segregation", "of", "MYOC", "Q48H", "(", "1q24.3-q25.2", ")", ",", "a", "mutation", "known", "to", "be", "associated", "with", "glaucoma", "in", "India", ".", "Fine", "mapping", "and", "candidate", "gene", "analysis", "continues", "with", "the", "hope", "that", "characterizing", "the", "micocoria", "gene", "will", "lead", "to", "a", "better", "understanding", "of", "microcoria", "and", "glaucoma", "causation", ".", "The", "relationship", "between", "microcoria", ",", "glaucoma", ",", "and", "the", "MYOC", "Q48H", "mutation", "in", "this", "family", "is", "discussed", "." ]
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17177139
A novel mutation (E333D) in the thyroid hormone beta receptor causing resistance to thyroid hormone syndrome. Resistance to thyroid hormone (RTH) is an inherited syndrome characterized by elevated serum thyroid hormones (TH), failure to suppress pituitary thyroid stimulating hormone (TSH) secretion, and variable peripheral tissue responsiveness to TH. The disorder is associated with diverse mutations in the thyroid hormone beta receptor (TRbeta). Here, we report a novel natural RTH mutation (E333D) located in the large carboxy-terminal ligand binding domain of TRbeta. The mutation was identified in a 22-year-old French woman coming to medical attention because of an increasing overweight. Biochemical tests showed elevated free thyroxine (T4: 20.8 pg/ml (normal, 8.5-18)) and triiodothyronine (T3: 5.7 pg/ml (normal, 1.4-4)) in the serum, together with an inappropriately nonsuppressed TSH level of 4.7 mU/ml (normal, 0.4-4). Her father and her brother's serum tests also showed biochemical abnormalities consistent with RTH. Direct sequencing of the TRbeta gene revealed a heterozygous transition 1284A>C in exon 9 resulting in substitution of glutamic acid 333 by aspartic acid residue (E333D). Further functional analyses of the novel TRbeta mutant were conducted. We found that the E333D mutation neither significantly affected the affinity of the receptor for T3 nor modified heterodimer formation with retinoid X receptor (RXR) when bound to DNA. However, in transient transfection assays, the E333D TRbeta mutant exhibited impaired transcriptional regulation on two distinct positively regulated thyroid response elements (F2- and DR4-TREs) as well as on the negatively regulated human TSHalpha promoter. Moreover, a dominant inhibition of the wild-type TRbeta counterpart transactivation function was observed on both a positive (F2-TRE) and a negative (TSHalpha) promoter. These results strongly suggest that the E333D TRbeta mutation is responsible for the RTH phenotype in the proposita's family.
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17634480
Common germline genetic variation in antioxidant defense genes and survival after diagnosis of breast cancer. PURPOSE: The prognosis of breast cancer varies considerably among individuals, and inherited genetic factors may help explain this variability. Of particular interest are genes involved in defense against reactive oxygen species (ROS) because ROS are thought to cause DNA damage and contribute to the pathogenesis of cancer. PATIENTS AND METHODS: We examined associations between 54 polymorphisms that tag the known common variants (minor allele frequency > 0.05) in 10 genes involved in oxidative damage repair (CAT, SOD1, SOD2, GPX1, GPX4, GSR, TXN, TXN2, TXNRD1, and TXNRD2) and survival in 4,470 women with breast cancer. RESULTS: Two single nucleotide polymorphisms (SNPs) in GPX4 (rs713041 and rs757229) were associated with all-cause mortality even after adjusting for multiple hypothesis testing (adjusted P = .0041 and P = .0035). These SNPs are correlated with each other (r2 = 0.61). GPX4 rs713041 is located near the selenocysteine insertion sequence element in the GPX4 3' untranslated region, and the rare allele of this SNP is associated with an increased risk of death, with a hazard ratio of 1.27 per rare allele carried (95% CI, 1.13 to 11.43). This effect was not attenuated after adjusting for tumor stage, grade, or estrogen receptor status. We found that the common allele is preferentially expressed in normal lymphocytes, normal breast, and breast tumors compared with the rare allele, but there were no differences in total levels of GPX4 mRNA across genotypes. CONCLUSION: These data provide strong support for the hypothesis that common variation in GPX4 is associated with prognosis after a diagnosis of breast cancer.
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15748645
Photochemoprevention of ultraviolet B signaling and photocarcinogenesis. Exposure to solar radiation, particularly its ultraviolet (UV) B component, has a variety of harmful effects on human health. Some of these effects include sunburn cell formation, basal and squamous cell cancers, melanoma, cataracts, photoaging of the skin, and immune suppression. Amongst these various adverse effects of UV radiation, skin cancer is of the greatest concern. Over the years, changes in lifestyle has led to a significant increase in the amount of UV radiation that people receive, and this consequently has led to a surge in the incidence of skin cancer. The development of skin cancer is a complex multistage phenomenon involving three distinct stages exemplified by initiation, promotion and progression stages. Each of these stages is mediated via alterations in various cellular, biochemical, and molecular changes. Initiation, the first step in the carcinogenesis process is essentially an irreversible step in which genetic alterations occur in genes that ultimately leads to DNA modification and fixation of mutation. Tumor promotion is the essential process in cancer development involving clonal expansion of initiated cells giving rise to pre-malignant and then to malignant lesions, essentially by alterations in signal transduction pathways. Tumor progression involves the conversion of pre-malignant and malignant lesions into an invasive and potentially metastatic malignant tumor. All these processes for skin cancer development involve stimulation of DNA synthesis, DNA damage and proliferation, inflammation, immunosuppression, epidermal hyperplasia, cell cycle dysregulation, depletion of antioxidant defenses, impairment of signal transduction pathways, induction of cyclooxygenase, increase in prostaglandin synthesis, and induction of ornithine decarboxylase. Photochemoprevention has been appreciated as a viable approach to reduce the occurrence of skin cancer and in recent years, the use of agents, especially botanical antioxidants, present in the common diet and beverages consumed by human population have gained considerable attention as photochemopreventive agents for human use. Many such agents have also found a place in skin care products. Although this is more common in oriental countries, its popularity is significantly growing in western countries. In this article, we have summarized the available information of laboratory studies on UVB-mediated signaling that can be exploited as targets for photochemoprevention. We suggest that the use of skin care products supplemented with proven chemopreventive agents in conjunction with the use of sunscreens along with educational efforts may be an effective strategy for reducing UV-induced photodamage and skin cancer in humans. The mechanistic basis for the use of such products is discussed.
[ "Photochemoprevention", "of", "ultraviolet", "B", "signaling", "and", "photocarcinogenesis", ".", "Exposure", "to", "solar", "radiation", ",", "particularly", "its", "ultraviolet", "(", "UV", ")", "B", "component", ",", "has", "a", "variety", "of", "harmful", "effects", "on", "human", "health", ".", "Some", "of", "these", "effects", "include", "sunburn", "cell", "formation", ",", "basal", "and", "squamous", "cell", "cancers", ",", "melanoma", ",", "cataracts", ",", "photoaging", "of", "the", "skin", ",", "and", "immune", "suppression", ".", "Amongst", "these", "various", "adverse", "effects", "of", "UV", "radiation", ",", "skin", "cancer", "is", "of", "the", "greatest", "concern", ".", "Over", "the", "years", ",", "changes", "in", "lifestyle", "has", "led", "to", "a", "significant", "increase", "in", "the", "amount", "of", "UV", "radiation", "that", "people", "receive", ",", "and", "this", "consequently", "has", "led", "to", "a", "surge", "in", "the", "incidence", "of", "skin", "cancer", ".", "The", "development", "of", "skin", "cancer", "is", "a", "complex", "multistage", "phenomenon", "involving", "three", "distinct", "stages", "exemplified", "by", "initiation", ",", "promotion", "and", "progression", "stages", ".", "Each", "of", "these", "stages", "is", "mediated", "via", "alterations", "in", "various", "cellular", ",", "biochemical", ",", "and", "molecular", "changes", ".", "Initiation", ",", "the", "first", "step", "in", "the", "carcinogenesis", "process", "is", "essentially", "an", "irreversible", "step", "in", "which", "genetic", "alterations", "occur", "in", "genes", "that", "ultimately", "leads", "to", "DNA", "modification", "and", "fixation", "of", "mutation", ".", "Tumor", "promotion", "is", "the", "essential", "process", "in", "cancer", "development", "involving", "clonal", "expansion", "of", "initiated", "cells", "giving", "rise", "to", "pre-malignant", "and", "then", "to", "malignant", "lesions", ",", "essentially", "by", "alterations", "in", "signal", "transduction", "pathways", ".", "Tumor", "progression", "involves", "the", "conversion", "of", "pre-malignant", "and", "malignant", "lesions", "into", "an", "invasive", "and", "potentially", "metastatic", "malignant", "tumor", ".", "All", "these", "processes", "for", "skin", "cancer", "development", "involve", "stimulation", "of", "DNA", "synthesis", ",", "DNA", "damage", "and", "proliferation", ",", "inflammation", ",", "immunosuppression", ",", "epidermal", "hyperplasia", ",", "cell", "cycle", "dysregulation", ",", "depletion", "of", "antioxidant", "defenses", ",", "impairment", "of", "signal", "transduction", "pathways", ",", "induction", "of", "cyclooxygenase", ",", "increase", "in", "prostaglandin", "synthesis", ",", "and", "induction", "of", "ornithine", "decarboxylase", ".", "Photochemoprevention", "has", "been", "appreciated", "as", "a", "viable", "approach", "to", "reduce", "the", "occurrence", "of", "skin", "cancer", "and", "in", "recent", "years", ",", "the", "use", "of", "agents", ",", "especially", "botanical", "antioxidants", ",", "present", "in", "the", "common", "diet", "and", "beverages", "consumed", "by", "human", "population", "have", "gained", "considerable", "attention", "as", "photochemopreventive", "agents", "for", "human", "use", ".", "Many", "such", "agents", "have", "also", "found", "a", "place", "in", "skin", "care", "products", ".", "Although", "this", "is", "more", "common", "in", "oriental", "countries", ",", "its", "popularity", "is", "significantly", "growing", "in", "western", "countries", ".", "In", "this", "article", ",", "we", "have", "summarized", "the", "available", "information", "of", "laboratory", "studies", "on", "UVB-mediated", "signaling", "that", "can", "be", "exploited", "as", "targets", "for", "photochemoprevention", ".", "We", "suggest", "that", "the", "use", "of", "skin", "care", "products", "supplemented", "with", "proven", "chemopreventive", "agents", "in", "conjunction", "with", "the", "use", "of", "sunscreens", "along", "with", "educational", "efforts", "may", "be", "an", "effective", "strategy", "for", "reducing", "UV-induced", "photodamage", "and", "skin", "cancer", "in", "humans", ".", "The", "mechanistic", "basis", "for", "the", "use", "of", "such", "products", "is", "discussed", "." ]
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16543197
A G1103R mutation in CRB1 is co-inherited with high hyperopia and Leber congenital amaurosis. PURPOSE: To identify the genetic basis of recessive inheritance of high hyperopia and Leber congenital amaurosis (LCA) in a family of Middle Eastern origin. MATERIALS AND METHODS: The patients were examined using standard ophthalmic techniques. DNA samples were obtained and genetic linkage was carried out using polymorphic markers flanking the known genes and loci for LCA. Exons were amplified and sequenced. RESULTS: All four members of this family affected by LCA showed high to extreme hyperopia, with average spherical refractive errors ranging from +5.00 to +10.00. Linkage was obtained to 1q31.3 with a maximal LOD score of 5.20 and a mutation found in exon 9 of the CRB1 gene, causing a G1103R substitution at a highly conserved site in the protein. CRB1 is a vertebrate homolog of the Drosophila crumbs gene, which is required for photoreceptor morphogenesis, and has been associated with either retinitis pigmentosa (RP) or LCA. This sequence variant has previously been reported as a compound heterozygote in one sporadic LCA patient. CONCLUSION: Although hyperopia has been associated with LCA, it is typically moderate and variable between patients with the same mutation. In addition, some CRB1 mutations can be associated with either RP or LCA. We have shown that hyperopia and LCA are linked to the mutant CRB1 gene itself and are not dependent on unlinked modifiers.
[ "A", "G1103R", "mutation", "in", "CRB1", "is", "co-inherited", "with", "high", "hyperopia", "and", "Leber", "congenital", "amaurosis", ".", "PURPOSE", ":", "To", "identify", "the", "genetic", "basis", "of", "recessive", "inheritance", "of", "high", "hyperopia", "and", "Leber", "congenital", "amaurosis", "(", "LCA", ")", "in", "a", "family", "of", "Middle", "Eastern", "origin", ".", "MATERIALS", "AND", "METHODS", ":", "The", "patients", "were", "examined", "using", "standard", "ophthalmic", "techniques", ".", "DNA", "samples", "were", "obtained", "and", "genetic", "linkage", "was", "carried", "out", "using", "polymorphic", "markers", "flanking", "the", "known", "genes", "and", "loci", "for", "LCA", ".", "Exons", "were", "amplified", "and", "sequenced", ".", "RESULTS", ":", "All", "four", "members", "of", "this", "family", "affected", "by", "LCA", "showed", "high", "to", "extreme", "hyperopia", ",", "with", "average", "spherical", "refractive", "errors", "ranging", "from", "+5.00", "to", "+10.00", ".", "Linkage", "was", "obtained", "to", "1q31.3", "with", "a", "maximal", "LOD", "score", "of", "5.20", "and", "a", "mutation", "found", "in", "exon", "9", "of", "the", "CRB1", "gene", ",", "causing", "a", "G1103R", "substitution", "at", "a", "highly", "conserved", "site", "in", "the", "protein", ".", "CRB1", "is", "a", "vertebrate", "homolog", "of", "the", "Drosophila", "crumbs", "gene", ",", "which", "is", "required", "for", "photoreceptor", "morphogenesis", ",", "and", "has", "been", "associated", "with", "either", "retinitis", "pigmentosa", "(", "RP", ")", "or", "LCA", ".", "This", "sequence", "variant", "has", "previously", "been", "reported", "as", "a", "compound", "heterozygote", "in", "one", "sporadic", "LCA", "patient", ".", "CONCLUSION", ":", "Although", "hyperopia", "has", "been", "associated", "with", "LCA", ",", "it", "is", "typically", "moderate", "and", "variable", "between", "patients", "with", "the", "same", "mutation", ".", "In", "addition", ",", "some", "CRB1", "mutations", "can", "be", "associated", "with", "either", "RP", "or", "LCA", ".", "We", "have", "shown", "that", "hyperopia", "and", "LCA", "are", "linked", "to", "the", "mutant", "CRB1", "gene", "itself", "and", "are", "not", "dependent", "on", "unlinked", "modifiers", "." ]
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20477932
Cocaine causes memory and learning impairments in rats: involvement of nuclear factor kappa B and oxidative stress, and prevention by topiramate. Different mechanisms have been suggested for cocaine toxicity including an increase in oxidative stress but the association between oxidative status in the brain and cocaine induced-behaviour is poorly understood. Nuclear factor kappa B (NFkappaB) is a sensor of oxidative stress and participates in memory formation that could be involved in drug toxicity and addiction mechanisms. Therefore NFkappaB activity, oxidative stress, neuronal nitric oxide synthase (nNOS) activity, spatial learning and memory as well as the effect of topiramate, a previously proposed therapy for cocaine addiction, were evaluated in an experimental model of cocaine administration in rats. NFkappaB activity was decreased in the frontal cortex of cocaine treated rats, as well as GSH concentration and glutathione peroxidase activity in the hippocampus, whereas nNOS activity in the hippocampus was increased. Memory retrieval of experiences acquired prior to cocaine administration was impaired and negatively correlated with NFkappaB activity in the frontal cortex. In contrast, learning of new tasks was enhanced and correlated with the increase of nNOS activity and the decrease of glutathione peroxidase. These results provide evidence for a possible mechanistic role of oxidative and nitrosative stress and NFkappaB in the alterations induced by cocaine. Topiramate prevented all the alterations observed, showing novel neuroprotective properties.
[ "Cocaine", "causes", "memory", "and", "learning", "impairments", "in", "rats", ":", "involvement", "of", "nuclear", "factor", "kappa", "B", "and", "oxidative", "stress", ",", "and", "prevention", "by", "topiramate", ".", "Different", "mechanisms", "have", "been", "suggested", "for", "cocaine", "toxicity", "including", "an", "increase", "in", "oxidative", "stress", "but", "the", "association", "between", "oxidative", "status", "in", "the", "brain", "and", "cocaine", "induced-behaviour", "is", "poorly", "understood", ".", "Nuclear", "factor", "kappa", "B", "(", "NFkappaB", ")", "is", "a", "sensor", "of", "oxidative", "stress", "and", "participates", "in", "memory", "formation", "that", "could", "be", "involved", "in", "drug", "toxicity", "and", "addiction", "mechanisms", ".", "Therefore", "NFkappaB", "activity", ",", "oxidative", "stress", ",", "neuronal", "nitric", "oxide", "synthase", "(", "nNOS", ")", "activity", ",", "spatial", "learning", "and", "memory", "as", "well", "as", "the", "effect", "of", "topiramate", ",", "a", "previously", "proposed", "therapy", "for", "cocaine", "addiction", ",", "were", "evaluated", "in", "an", "experimental", "model", "of", "cocaine", "administration", "in", "rats", ".", "NFkappaB", "activity", "was", "decreased", "in", "the", "frontal", "cortex", "of", "cocaine", "treated", "rats", ",", "as", "well", "as", "GSH", "concentration", "and", "glutathione", "peroxidase", "activity", "in", "the", "hippocampus", ",", "whereas", "nNOS", "activity", "in", "the", "hippocampus", "was", "increased", ".", "Memory", "retrieval", "of", "experiences", "acquired", "prior", "to", "cocaine", "administration", "was", "impaired", "and", "negatively", "correlated", "with", "NFkappaB", "activity", "in", "the", "frontal", "cortex", ".", "In", "contrast", ",", "learning", "of", "new", "tasks", "was", "enhanced", "and", "correlated", "with", "the", "increase", "of", "nNOS", "activity", "and", "the", "decrease", "of", "glutathione", "peroxidase", ".", "These", "results", "provide", "evidence", "for", "a", "possible", "mechanistic", "role", "of", "oxidative", "and", "nitrosative", "stress", "and", "NFkappaB", "in", "the", "alterations", "induced", "by", "cocaine", ".", "Topiramate", "prevented", "all", "the", "alterations", "observed", ",", "showing", "novel", "neuroprotective", "properties", "." ]
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28348168
FGFR2 is required for airway basal cell self-renewal and terminal differentiation. Airway stem cells slowly self-renew and produce differentiated progeny to maintain homeostasis throughout the lifespan of an individual. Mutations in the molecular regulators of these processes may drive cancer or degenerative disease, but are also potential therapeutic targets. Conditionally deleting one copy of FGF receptor 2 (FGFR2) in adult mouse airway basal cells results in self-renewal and differentiation phenotypes. We show that FGFR2 signalling correlates with maintenance of expression of a key transcription factor for basal cell self-renewal and differentiation: SOX2. This heterozygous phenotype illustrates that subtle changes in receptor tyrosine kinase signalling can have significant effects, perhaps providing an explanation for the numerous changes seen in cancer.
[ "FGFR2", "is", "required", "for", "airway", "basal", "cell", "self-renewal", "and", "terminal", "differentiation", ".", "Airway", "stem", "cells", "slowly", "self-renew", "and", "produce", "differentiated", "progeny", "to", "maintain", "homeostasis", "throughout", "the", "lifespan", "of", "an", "individual", ".", "Mutations", "in", "the", "molecular", "regulators", "of", "these", "processes", "may", "drive", "cancer", "or", "degenerative", "disease", ",", "but", "are", "also", "potential", "therapeutic", "targets", ".", "Conditionally", "deleting", "one", "copy", "of", "FGF", "receptor", "2", "(", "FGFR2", ")", "in", "adult", "mouse", "airway", "basal", "cells", "results", "in", "self-renewal", "and", "differentiation", "phenotypes", ".", "We", "show", "that", "FGFR2", "signalling", "correlates", "with", "maintenance", "of", "expression", "of", "a", "key", "transcription", "factor", "for", "basal", "cell", "self-renewal", "and", "differentiation", ":", "SOX2", ".", "This", "heterozygous", "phenotype", "illustrates", "that", "subtle", "changes", "in", "receptor", "tyrosine", "kinase", "signalling", "can", "have", "significant", "effects", ",", "perhaps", "providing", "an", "explanation", "for", "the", "numerous", "changes", "seen", "in", "cancer", "." ]
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16418600
Genetic investigation of the TSPYL1 gene in sudden infant death syndrome. BACKGROUND: Sudden infant death syndrome (SIDS) constitutes the most frequent cause of death in the postperinatal period in Germany. Recently, a lethal phenotype characterized by sudden infant death with dysgenesis of the testes syndrome (SIDDT) was identified to be caused by loss of function mutations in the TSPYL1 gene. PURPOSE: The study's purpose was to reveal a possible role of TSPYL1 in SIDS. METHODS: DNA samples of 126 SIDS cases and 261 controls were investigated. RESULTS: We found five sequence variations, each of them causing an amino acid substitution. No Hardy Weinberg disequilibrium and no significant difference in allele frequencies between patients and controls were observed for any variation. In one female patient a p.F366L amino acid polymorphism was found heterozygous, which could not be displayed in controls. A pathogenic implication of this substitution, which is conserved in primates and rodents, cannot be ruled out completely. Because SIDDT is the result of homozygous TSPYL1 mutations, this heterozygous exchange cannot solely explain the sudden death in this child. The reported mutation associated with SIDDT (457_458insG) was not detectable in our cohort. CONCLUSION: No association of sequence variations in the TSPYL1 gene and SIDS has been found in a German cohort. Genetic analysis of TSPYL1 seems to be of limited significance in the differential diagnosis of SIDS without dysgenesis of the testes.
[ "Genetic", "investigation", "of", "the", "TSPYL1", "gene", "in", "sudden", "infant", "death", "syndrome", ".", "BACKGROUND", ":", "Sudden", "infant", "death", "syndrome", "(", "SIDS", ")", "constitutes", "the", "most", "frequent", "cause", "of", "death", "in", "the", "postperinatal", "period", "in", "Germany", ".", "Recently", ",", "a", "lethal", "phenotype", "characterized", "by", "sudden", "infant", "death", "with", "dysgenesis", "of", "the", "testes", "syndrome", "(", "SIDDT", ")", "was", "identified", "to", "be", "caused", "by", "loss", "of", "function", "mutations", "in", "the", "TSPYL1", "gene", ".", "PURPOSE", ":", "The", "study", "'s", "purpose", "was", "to", "reveal", "a", "possible", "role", "of", "TSPYL1", "in", "SIDS", ".", "METHODS", ":", "DNA", "samples", "of", "126", "SIDS", "cases", "and", "261", "controls", "were", "investigated", ".", "RESULTS", ":", "We", "found", "five", "sequence", "variations", ",", "each", "of", "them", "causing", "an", "amino", "acid", "substitution", ".", "No", "Hardy", "Weinberg", "disequilibrium", "and", "no", "significant", "difference", "in", "allele", "frequencies", "between", "patients", "and", "controls", "were", "observed", "for", "any", "variation", ".", "In", "one", "female", "patient", "a", "p.F366L", "amino", "acid", "polymorphism", "was", "found", "heterozygous", ",", "which", "could", "not", "be", "displayed", "in", "controls", ".", "A", "pathogenic", "implication", "of", "this", "substitution", ",", "which", "is", "conserved", "in", "primates", "and", "rodents", ",", "can", "not", "be", "ruled", "out", "completely", ".", "Because", "SIDDT", "is", "the", "result", "of", "homozygous", "TSPYL1", "mutations", ",", "this", "heterozygous", "exchange", "can", "not", "solely", "explain", "the", "sudden", "death", "in", "this", "child", ".", "The", "reported", "mutation", "associated", "with", "SIDDT", "(", "457_458insG", ")", "was", "not", "detectable", "in", "our", "cohort", ".", "CONCLUSION", ":", "No", "association", "of", "sequence", "variations", "in", "the", "TSPYL1", "gene", "and", "SIDS", "has", "been", "found", "in", "a", "German", "cohort", ".", "Genetic", "analysis", "of", "TSPYL1", "seems", "to", "be", "of", "limited", "significance", "in", "the", "differential", "diagnosis", "of", "SIDS", "without", "dysgenesis", "of", "the", "testes", "." ]
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16904497
Cauda equina syndrome after epidural steroid injection: a case report. OBJECTIVE: Conventional treatment methods of lumbusacral radiculopathy are physical therapy, epidural steroid injections, oral medications, and spinal manipulative therapy. Cauda equina syndrome is a rare complication of epidural anesthesia. The following case is a report of cauda equina syndrome possibly caused by epidural injection of triamcinolone and bupivacaine. CLINICAL FEATURES: A 50-year-old woman with low back and right leg pain was scheduled for epidural steroid injection. INTERVENTION AND OUTCOME: An 18-gauge Touhy needle was inserted until loss of resistance occurred at the L4-5 level. Spread of the contrast medium within the epidural space was determined by radiographic imaging. After verifying the epidural space, bupivacaine and triamcinolone diacetate were injected. After the injection, there was a reduction in radicular symptoms. Three hours later, she complained of perineal numbness and lower extremity weakness. The neurologic evaluation revealed loss of sensation in the saddle area and medial aspect of her right leg. There was a decrease in the perception of pinprick test. Deep-tendon reflexes were decreased especially in the right leg. She was unable to urinate. The patient's symptoms improved slightly over the next few hours. She had a gradual return of motor function and ability of feeling Foley catheter. All of the symptoms were completely resolved over the next 8 hours. CONCLUSION: Complications associated with epidural steroid injections are rare. Clinical examination and continued vigilance for neurologic deterioration after epidural steroid injections is important.
[ "Cauda", "equina", "syndrome", "after", "epidural", "steroid", "injection", ":", "a", "case", "report", ".", "OBJECTIVE", ":", "Conventional", "treatment", "methods", "of", "lumbusacral", "radiculopathy", "are", "physical", "therapy", ",", "epidural", "steroid", "injections", ",", "oral", "medications", ",", "and", "spinal", "manipulative", "therapy", ".", "Cauda", "equina", "syndrome", "is", "a", "rare", "complication", "of", "epidural", "anesthesia", ".", "The", "following", "case", "is", "a", "report", "of", "cauda", "equina", "syndrome", "possibly", "caused", "by", "epidural", "injection", "of", "triamcinolone", "and", "bupivacaine", ".", "CLINICAL", "FEATURES", ":", "A", "50-year-old", "woman", "with", "low", "back", "and", "right", "leg", "pain", "was", "scheduled", "for", "epidural", "steroid", "injection", ".", "INTERVENTION", "AND", "OUTCOME", ":", "An", "18-gauge", "Touhy", "needle", "was", "inserted", "until", "loss", "of", "resistance", "occurred", "at", "the", "L4-5", "level", ".", "Spread", "of", "the", "contrast", "medium", "within", "the", "epidural", "space", "was", "determined", "by", "radiographic", "imaging", ".", "After", "verifying", "the", "epidural", "space", ",", "bupivacaine", "and", "triamcinolone", "diacetate", "were", "injected", ".", "After", "the", "injection", ",", "there", "was", "a", "reduction", "in", "radicular", "symptoms", ".", "Three", "hours", "later", ",", "she", "complained", "of", "perineal", "numbness", "and", "lower", "extremity", "weakness", ".", "The", "neurologic", "evaluation", "revealed", "loss", "of", "sensation", "in", "the", "saddle", "area", "and", "medial", "aspect", "of", "her", "right", "leg", ".", "There", "was", "a", "decrease", "in", "the", "perception", "of", "pinprick", "test", ".", "Deep-tendon", "reflexes", "were", "decreased", "especially", "in", "the", "right", "leg", ".", "She", "was", "unable", "to", "urinate", ".", "The", "patient", "'s", "symptoms", "improved", "slightly", "over", "the", "next", "few", "hours", ".", "She", "had", "a", "gradual", "return", "of", "motor", "function", "and", "ability", "of", "feeling", "Foley", "catheter", ".", "All", "of", "the", "symptoms", "were", "completely", "resolved", "over", "the", "next", "8", "hours", ".", "CONCLUSION", ":", "Complications", "associated", "with", "epidural", "steroid", "injections", "are", "rare", ".", "Clinical", "examination", "and", "continued", "vigilance", "for", "neurologic", "deterioration", "after", "epidural", "steroid", "injections", "is", "important", "." ]
[ "2", "2", "2", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "3", "0", "3", "0", "0", "0", "0", "0", "0", "4", "0", "2", "2", "2", "2", "2", "2", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "3", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "2", "2", "2", "0", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "3", "0", "0", "0", "0" ]
17083016
Genetic polymorphism of the binding domain of surfactant protein-A2 increases susceptibility to meningococcal disease. BACKGROUND: Meningococcal disease occurs after colonization of the nasopharynx with Neisseria meningitidis. Surfactant protein (SP)-A and SP-D are pattern-recognition molecules of the respiratory tract that activate inflammatory and phagocytic defences after binding to microbial sugars. Variation in the genes of the surfactant proteins affects the expression and function of these molecules. METHODS: Allele frequencies of SP-A1, SP-A2, and SP-D were determined by polymerase chain reaction in 303 patients with microbiologically proven meningococcal disease, including 18 patients who died, and 222 healthy control subjects. RESULTS: Homozygosity of allele 1A1 of SP-A2 increased the risk of meningococcal disease (odds ratio [OR], 7.4; 95% confidence interval [CI], 1.3-42.4); carriage of 1A5 reduced the risk (OR, 0.3; 95% CI, 0.1-0.97). An analysis of the multiple single-nucleotide polymorphisms in SP-A demonstrated that homozygosity for alleles encoding lysine (in 1A1) rather than glutamine (in 1A5) at amino acid 223 in the carbohydrate recognition domain was associated with an increased risk of meningococcal disease (OR, 6.7; 95% CI, 1.4-31.5). Carriage of alleles encoding lysine at residue 223 was found in 61% of patients who died, compared with 35% of those who survived (OR adjusted for age, 2.9; 95% CI, 1.1-7.7). Genetic variation of SP-A1 and SP-D was not associated with meningococcal disease. CONCLUSIONS: Gene polymorphism resulting in the substitution of glutamine with lysine at residue 223 in the carbohydrate recognition domain of SP-A2 increases susceptibility to meningococcal disease, as well as the risk of death.
[ "Genetic", "polymorphism", "of", "the", "binding", "domain", "of", "surfactant", "protein-A2", "increases", "susceptibility", "to", "meningococcal", "disease", ".", "BACKGROUND", ":", "Meningococcal", "disease", "occurs", "after", "colonization", "of", "the", "nasopharynx", "with", "Neisseria", "meningitidis", ".", "Surfactant", "protein", "(", "SP", ")", "-A", "and", "SP-D", "are", "pattern-recognition", "molecules", "of", "the", "respiratory", "tract", "that", "activate", "inflammatory", "and", "phagocytic", "defences", "after", "binding", "to", "microbial", "sugars", ".", "Variation", "in", "the", "genes", "of", "the", "surfactant", "proteins", "affects", "the", "expression", "and", "function", "of", "these", "molecules", ".", "METHODS", ":", "Allele", "frequencies", "of", "SP-A1", ",", "SP-A2", ",", "and", "SP-D", "were", "determined", "by", "polymerase", "chain", "reaction", "in", "303", "patients", "with", "microbiologically", "proven", "meningococcal", "disease", ",", "including", "18", "patients", "who", "died", ",", "and", "222", "healthy", "control", "subjects", ".", "RESULTS", ":", "Homozygosity", "of", "allele", "1A1", "of", "SP-A2", "increased", "the", "risk", "of", "meningococcal", "disease", "(", "odds", "ratio", "[", "OR", "]", ",", "7.4", ";", "95", "%", "confidence", "interval", "[", "CI", "]", ",", "1.3-42.4", ")", ";", "carriage", "of", "1A5", "reduced", "the", "risk", "(", "OR", ",", "0.3", ";", "95", "%", "CI", ",", "0.1-0.97", ")", ".", "An", "analysis", "of", "the", "multiple", "single-nucleotide", "polymorphisms", "in", "SP-A", "demonstrated", "that", "homozygosity", "for", "alleles", "encoding", "lysine", "(", "in", "1A1", ")", "rather", "than", "glutamine", "(", "in", "1A5", ")", "at", "amino", "acid", "223", "in", "the", "carbohydrate", "recognition", "domain", "was", "associated", "with", "an", "increased", "risk", "of", "meningococcal", "disease", "(", "OR", ",", "6.7", ";", "95", "%", "CI", ",", "1.4-31.5", ")", ".", "Carriage", "of", "alleles", "encoding", "lysine", "at", "residue", "223", "was", "found", "in", "61", "%", "of", "patients", "who", "died", ",", "compared", "with", "35", "%", "of", "those", "who", "survived", "(", "OR", "adjusted", "for", "age", ",", "2.9", ";", "95", "%", "CI", ",", "1.1-7.7", ")", ".", "Genetic", "variation", "of", "SP-A1", "and", "SP-D", "was", "not", "associated", "with", "meningococcal", "disease", ".", "CONCLUSIONS", ":", "Gene", "polymorphism", "resulting", "in", "the", "substitution", "of", "glutamine", "with", "lysine", "at", "residue", "223", "in", "the", "carbohydrate", "recognition", "domain", "of", "SP-A2", "increases", "susceptibility", "to", "meningococcal", "disease", ",", "as", "well", "as", "the", "risk", "of", "death", "." ]
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17910065
A novel missense mutation in the paired domain of human PAX9 causes oligodontia. PAX9 and MSX1 are transcription factors that play essential roles in craniofacial and limb development. In humans, mutations in both genes are associated with nonsyndromic and syndromic oligodontia, respectively. We screened one family with nonsyndromic oligodontia for mutations in PAX9 and MSX1. Single stranded conformational polymorphism (SSCP) analysis and sequencing revealed a novel heterozygous C139T transition in PAX9 in the affected members of the family. There were no mutations detected in the entire coding sequence of MSX1. The C139T mutation, predicted to result in the substitution of an arginine by a tryptophan (R47W) in the N-terminal subdomain, affected conserved residues in the PAX9 paired domain. To elucidate the pathogenic mechanism producing oligodontia phenotype caused by this mutation, we analyzed the binding of wild-type and mutant PAX9 paired domain protein to double-stranded DNA targets. The R47W mutation dramatically reduced DNA binding suggesting that the mutant protein with consequent haploinsufficiency results in a clinical phenotype.
[ "A", "novel", "missense", "mutation", "in", "the", "paired", "domain", "of", "human", "PAX9", "causes", "oligodontia", ".", "PAX9", "and", "MSX1", "are", "transcription", "factors", "that", "play", "essential", "roles", "in", "craniofacial", "and", "limb", "development", ".", "In", "humans", ",", "mutations", "in", "both", "genes", "are", "associated", "with", "nonsyndromic", "and", "syndromic", "oligodontia", ",", "respectively", ".", "We", "screened", "one", "family", "with", "nonsyndromic", "oligodontia", "for", "mutations", "in", "PAX9", "and", "MSX1", ".", "Single", "stranded", "conformational", "polymorphism", "(", "SSCP", ")", "analysis", "and", "sequencing", "revealed", "a", "novel", "heterozygous", "C139T", "transition", "in", "PAX9", "in", "the", "affected", "members", "of", "the", "family", ".", "There", "were", "no", "mutations", "detected", "in", "the", "entire", "coding", "sequence", "of", "MSX1", ".", "The", "C139T", "mutation", ",", "predicted", "to", "result", "in", "the", "substitution", "of", "an", "arginine", "by", "a", "tryptophan", "(", "R47W", ")", "in", "the", "N-terminal", "subdomain", ",", "affected", "conserved", "residues", "in", "the", "PAX9", "paired", "domain", ".", "To", "elucidate", "the", "pathogenic", "mechanism", "producing", "oligodontia", "phenotype", "caused", "by", "this", "mutation", ",", "we", "analyzed", "the", "binding", "of", "wild-type", "and", "mutant", "PAX9", "paired", "domain", "protein", "to", "double-stranded", "DNA", "targets", ".", "The", "R47W", "mutation", "dramatically", "reduced", "DNA", "binding", "suggesting", "that", "the", "mutant", "protein", "with", "consequent", "haploinsufficiency", "results", "in", "a", "clinical", "phenotype", "." ]
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20846357
A novel mutation in the connexin 26 gene (GJB2) in a child with clinical and histological features of keratitis-ichthyosis-deafness (KID) syndrome. BACKGROUND: Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital ectodermal disorder, caused by heterozygous missense mutation in GJB2, encoding the gap junction protein connexin 26. The commonest mutation is the p.Asp50Asn mutation, and only a few other mutations have been described to date. AIM: To report the fatal clinical course and characterize the genetic background of a premature male neonate with the clinical and histological features of KID syndrome. METHODS: Genomic DNA was extracted from peripheral blood and used for PCR amplification of the GJB2 gene. Direct sequencing was used for mutation analysis. RESULTS: The clinical features included hearing impairment, ichthyosiform erythroderma with hyperkeratotic plaques, palmoplantar keratoderma, alopecia of the scalp and eyelashes, and a thick vernix caseosa-like covering of the scalp. On histological analysis, features characteristic of KID syndrome, such as acanthosis and papillomatosis of the epidermis with basket-weave hyperkeratosis, were seen. The skin symptoms were treated successfully with acitretin 0.5 mg/kg. The boy developed intraventricular and intracerebral haemorrhage, leading to hydrocephalus. His condition was further complicated by septicaemia and meningitis caused by infection with extended-spectrum beta-lactamase-producing Klebsiella pneumoniae. Severe respiratory failure followed, and the child died at 46 weeks of gestational age (13 weeks postnatally). Sequencing of the GJB2 gene showed that the child was heterozygous for a novel nucleotide change, c.263C>T, in exon 2, leading to a substitution of alanine for valine at position 88 (p.Ala88Val). CONCLUSIONS: This study has identified a new heterozygous de novo mutation in the Cx26 gene (c.263C>T; p.Ala88Val) leading to KID syndrome.
[ "A", "novel", "mutation", "in", "the", "connexin", "26", "gene", "(", "GJB2", ")", "in", "a", "child", "with", "clinical", "and", "histological", "features", "of", "keratitis-ichthyosis-deafness", "(", "KID", ")", "syndrome", ".", "BACKGROUND", ":", "Keratitis-ichthyosis-deafness", "(", "KID", ")", "syndrome", "is", "a", "rare", "congenital", "ectodermal", "disorder", ",", "caused", "by", "heterozygous", "missense", "mutation", "in", "GJB2", ",", "encoding", "the", "gap", "junction", "protein", "connexin", "26", ".", "The", "commonest", "mutation", "is", "the", "p.Asp50Asn", "mutation", ",", "and", "only", "a", "few", "other", "mutations", "have", "been", "described", "to", "date", ".", "AIM", ":", "To", "report", "the", "fatal", "clinical", "course", "and", "characterize", "the", "genetic", "background", "of", "a", "premature", "male", "neonate", "with", "the", "clinical", "and", "histological", "features", "of", "KID", "syndrome", ".", "METHODS", ":", "Genomic", "DNA", "was", "extracted", "from", "peripheral", "blood", "and", "used", "for", "PCR", "amplification", "of", "the", "GJB2", "gene", ".", "Direct", "sequencing", "was", "used", "for", "mutation", "analysis", ".", "RESULTS", ":", "The", "clinical", "features", "included", "hearing", "impairment", ",", "ichthyosiform", "erythroderma", "with", "hyperkeratotic", "plaques", ",", "palmoplantar", "keratoderma", ",", "alopecia", "of", "the", "scalp", "and", "eyelashes", ",", "and", "a", "thick", "vernix", "caseosa-like", "covering", "of", "the", "scalp", ".", "On", "histological", "analysis", ",", "features", "characteristic", "of", "KID", "syndrome", ",", "such", "as", "acanthosis", "and", "papillomatosis", "of", "the", "epidermis", "with", "basket-weave", "hyperkeratosis", ",", "were", "seen", ".", "The", "skin", "symptoms", "were", "treated", "successfully", "with", "acitretin", "0.5", "mg/kg", ".", "The", "boy", "developed", "intraventricular", "and", "intracerebral", "haemorrhage", ",", "leading", "to", "hydrocephalus", ".", "His", "condition", "was", "further", "complicated", "by", "septicaemia", "and", "meningitis", "caused", "by", "infection", "with", "extended-spectrum", "beta-lactamase-producing", "Klebsiella", "pneumoniae", ".", "Severe", "respiratory", "failure", "followed", ",", "and", "the", "child", "died", "at", "46", "weeks", "of", "gestational", "age", "(", "13", "weeks", "postnatally", ")", ".", "Sequencing", "of", "the", "GJB2", "gene", "showed", "that", "the", "child", "was", "heterozygous", "for", "a", "novel", "nucleotide", "change", ",", "c.263C", ">", "T", ",", "in", "exon", "2", ",", "leading", "to", "a", "substitution", "of", "alanine", "for", "valine", "at", "position", "88", "(", "p.Ala88Val", ")", ".", "CONCLUSIONS", ":", "This", "study", "has", "identified", "a", "new", "heterozygous", "de", "novo", "mutation", "in", "the", "Cx26", "gene", "(", "c.263C", ">", "T", ";", "p.Ala88Val", ")", "leading", "to", "KID", "syndrome", "." ]
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26115410
Mechanisms Underlying Latent Disease Risk Associated with Early-Life Arsenic Exposure: Current Research Trends and Scientific Gaps. BACKGROUND: Millions of individuals worldwide, particularly those living in rural and developing areas, are exposed to harmful levels of inorganic arsenic (iAs) in their drinking water. Inorganic As exposure during key developmental periods is associated with a variety of adverse health effects including those that are evident in adulthood. There is considerable interest in identifying the molecular mechanisms that relate early-life iAs exposure to the development of these latent diseases, particularly in relationship to cancer. OBJECTIVES: This work summarizes research on the molecular mechanisms that underlie the increased risk of cancer development in adulthood that is associated with early-life iAs exposure. DISCUSSION: Epigenetic reprogramming that imparts functional changes in gene expression, the development of cancer stem cells, and immunomodulation are plausible underlying mechanisms by which early-life iAs exposure elicits latent carcinogenic effects. CONCLUSIONS: Evidence is mounting that relates early-life iAs exposure and cancer development later in life. Future research should include animal studies that address mechanistic hypotheses and studies of human populations that integrate early-life exposure, molecular alterations, and latent disease outcomes.
[ "Mechanisms", "Underlying", "Latent", "Disease", "Risk", "Associated", "with", "Early-Life", "Arsenic", "Exposure", ":", "Current", "Research", "Trends", "and", "Scientific", "Gaps", ".", "BACKGROUND", ":", "Millions", "of", "individuals", "worldwide", ",", "particularly", "those", "living", "in", "rural", "and", "developing", "areas", ",", "are", "exposed", "to", "harmful", "levels", "of", "inorganic", "arsenic", "(", "iAs", ")", "in", "their", "drinking", "water", ".", "Inorganic", "As", "exposure", "during", "key", "developmental", "periods", "is", "associated", "with", "a", "variety", "of", "adverse", "health", "effects", "including", "those", "that", "are", "evident", "in", "adulthood", ".", "There", "is", "considerable", "interest", "in", "identifying", "the", "molecular", "mechanisms", "that", "relate", "early-life", "iAs", "exposure", "to", "the", "development", "of", "these", "latent", "diseases", ",", "particularly", "in", "relationship", "to", "cancer", ".", "OBJECTIVES", ":", "This", "work", "summarizes", "research", "on", "the", "molecular", "mechanisms", "that", "underlie", "the", "increased", "risk", "of", "cancer", "development", "in", "adulthood", "that", "is", "associated", "with", "early-life", "iAs", "exposure", ".", "DISCUSSION", ":", "Epigenetic", "reprogramming", "that", "imparts", "functional", "changes", "in", "gene", "expression", ",", "the", "development", "of", "cancer", "stem", "cells", ",", "and", "immunomodulation", "are", "plausible", "underlying", "mechanisms", "by", "which", "early-life", "iAs", "exposure", "elicits", "latent", "carcinogenic", "effects", ".", "CONCLUSIONS", ":", "Evidence", "is", "mounting", "that", "relates", "early-life", "iAs", "exposure", "and", "cancer", "development", "later", "in", "life", ".", "Future", "research", "should", "include", "animal", "studies", "that", "address", "mechanistic", "hypotheses", "and", "studies", "of", "human", "populations", "that", "integrate", "early-life", "exposure", ",", "molecular", "alterations", ",", "and", "latent", "disease", "outcomes", "." ]
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15807692
Identification of novel type VII collagen gene mutations resulting in severe recessive dystrophic epidermolysis bullosa. In this work, we studied the proband in a small nuclear family of Chinese and Dutch/German descent and identified two novel mutations in the type VII collagen gene leading to recessive dystrophic epidermolysis bullosa, Hallopeau-Siemens variant (HS-RDEB). The maternal mutation is a single base pair deletion of a cytosine nucleotide in exon 26, designated 3472delC, resulting in a frameshift and a premature termination codon (PTC) within the same exon, 7 bp downstream of the site of the mutation. The paternal mutation is a G-->A transition located at the 5' donor splice site within intron 51, designated IVS51 + 1G-->A. This mutation leads to the activation of a cryptic splice site, 32 bp downstream of the mutation site and to subsequent aberrant out-of-frame splicing, resulting in two alternative mRNA transcripts and a downstream PTC. To our knowledge, these two mutations have not been previously reported. These findings extend the body of evidence for compound heterozygous mutations leading to HS-RDEB and provide the basis for prenatal diagnosis in this family.
[ "Identification", "of", "novel", "type", "VII", "collagen", "gene", "mutations", "resulting", "in", "severe", "recessive", "dystrophic", "epidermolysis", "bullosa", ".", "In", "this", "work", ",", "we", "studied", "the", "proband", "in", "a", "small", "nuclear", "family", "of", "Chinese", "and", "Dutch/German", "descent", "and", "identified", "two", "novel", "mutations", "in", "the", "type", "VII", "collagen", "gene", "leading", "to", "recessive", "dystrophic", "epidermolysis", "bullosa", ",", "Hallopeau-Siemens", "variant", "(", "HS-RDEB", ")", ".", "The", "maternal", "mutation", "is", "a", "single", "base", "pair", "deletion", "of", "a", "cytosine", "nucleotide", "in", "exon", "26", ",", "designated", "3472delC", ",", "resulting", "in", "a", "frameshift", "and", "a", "premature", "termination", "codon", "(", "PTC", ")", "within", "the", "same", "exon", ",", "7", "bp", "downstream", "of", "the", "site", "of", "the", "mutation", ".", "The", "paternal", "mutation", "is", "a", "G", "--", ">", "A", "transition", "located", "at", "the", "5", "'", "donor", "splice", "site", "within", "intron", "51", ",", "designated", "IVS51", "+", "1G", "--", ">", "A", ".", "This", "mutation", "leads", "to", "the", "activation", "of", "a", "cryptic", "splice", "site", ",", "32", "bp", "downstream", "of", "the", "mutation", "site", "and", "to", "subsequent", "aberrant", "out-of-frame", "splicing", ",", "resulting", "in", "two", "alternative", "mRNA", "transcripts", "and", "a", "downstream", "PTC", ".", "To", "our", "knowledge", ",", "these", "two", "mutations", "have", "not", "been", "previously", "reported", ".", "These", "findings", "extend", "the", "body", "of", "evidence", "for", "compound", "heterozygous", "mutations", "leading", "to", "HS-RDEB", "and", "provide", "the", "basis", "for", "prenatal", "diagnosis", "in", "this", "family", "." ]
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16157158
A Cys 23-Ser 23 substitution in the 5-HT(2C) receptor gene influences body weight regulation in females with seasonal affective disorder: an Austrian-Canadian collaborative study. Most females with seasonal affective disorder (SAD) exhibit atypical vegetative symptoms such as overeating, and weight gain when depressed. The serotonin 2C receptor (5-HT(2C)) plays a key role in control of appetite and satiety. A 5-HT(2C) Cys 23 Ser substitution, coded for by a single nucleotide polymorphism (Cys 23 Ser) within the 5-HT(2C) gene, has been shown to influence 5-HT(2C) function. We hypothesized that Cys 23 Ser influences weight regulation in females with SAD. Two independent samples from Austria (162 females with SAD, 119 controls), and Canada (90 females with SAD, 42 controls) were genotyped for Cys 23 Ser. Influence on weight regulation was analyzed within patients with atypical features. In Austrians, genotype distribution differed between patients and controls (p=0.044) and Cys 23 Ser was associated with weight (p=0.039), body mass index (BMI; p=0.038), and seasonal appetite change (p=0.031). All values were highest in Cys/Cys, intermediate in Cys/Ser, and lowest in Ser/Ser carriers. In Canadian patients, Cys 23 Ser was associated with minimum lifetime BMI (p=0.046), with lowest values in Ser/Ser carriers. Our data provide evidence that Cys 23 Ser mediates severity of weight regulation disturbances in females with SAD, and the gene-dose effect-like differences suggest a direct functional role of Cys 23 Ser in the behavioral regulation of body weight.
[ "A", "Cys", "23-Ser", "23", "substitution", "in", "the", "5-HT", "(", "2C", ")", "receptor", "gene", "influences", "body", "weight", "regulation", "in", "females", "with", "seasonal", "affective", "disorder", ":", "an", "Austrian-Canadian", "collaborative", "study", ".", "Most", "females", "with", "seasonal", "affective", "disorder", "(", "SAD", ")", "exhibit", "atypical", "vegetative", "symptoms", "such", "as", "overeating", ",", "and", "weight", "gain", "when", "depressed", ".", "The", "serotonin", "2C", "receptor", "(", "5-HT", "(", "2C", ")", ")", "plays", "a", "key", "role", "in", "control", "of", "appetite", "and", "satiety", ".", "A", "5-HT", "(", "2C", ")", "Cys", "23", "Ser", "substitution", ",", "coded", "for", "by", "a", "single", "nucleotide", "polymorphism", "(", "Cys", "23", "Ser", ")", "within", "the", "5-HT", "(", "2C", ")", "gene", ",", "has", "been", "shown", "to", "influence", "5-HT", "(", "2C", ")", "function", ".", "We", "hypothesized", "that", "Cys", "23", "Ser", "influences", "weight", "regulation", "in", "females", "with", "SAD", ".", "Two", "independent", "samples", "from", "Austria", "(", "162", "females", "with", "SAD", ",", "119", "controls", ")", ",", "and", "Canada", "(", "90", "females", "with", "SAD", ",", "42", "controls", ")", "were", "genotyped", "for", "Cys", "23", "Ser", ".", "Influence", "on", "weight", "regulation", "was", "analyzed", "within", "patients", "with", "atypical", "features", ".", "In", "Austrians", ",", "genotype", "distribution", "differed", "between", "patients", "and", "controls", "(", "p=0.044", ")", "and", "Cys", "23", "Ser", "was", "associated", "with", "weight", "(", "p=0.039", ")", ",", "body", "mass", "index", "(", "BMI", ";", "p=0.038", ")", ",", "and", "seasonal", "appetite", "change", "(", "p=0.031", ")", ".", "All", "values", "were", "highest", "in", "Cys/Cys", ",", "intermediate", "in", "Cys/Ser", ",", "and", "lowest", "in", "Ser/Ser", "carriers", ".", "In", "Canadian", "patients", ",", "Cys", "23", "Ser", "was", "associated", "with", "minimum", "lifetime", "BMI", "(", "p=0.046", ")", ",", "with", "lowest", "values", "in", "Ser/Ser", "carriers", ".", "Our", "data", "provide", "evidence", "that", "Cys", "23", "Ser", "mediates", "severity", "of", "weight", "regulation", "disturbances", "in", "females", "with", "SAD", ",", "and", "the", "gene-dose", "effect-like", "differences", "suggest", "a", "direct", "functional", "role", "of", "Cys", "23", "Ser", "in", "the", "behavioral", "regulation", "of", "body", "weight", "." ]
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17192049
Cytochrome p4501A1 gene variants as susceptibility marker for prostate cancer. CYP1A1 activates environmental procarcinogens and catalyzes oxidative metabolism of estrogens and is likely to play an important role in the etiology of prostate cancer. To evaluate this phenomenon, the association between two single nucleotide polymorphisms (A to G transition in exon7 leading to amino acid substitution Ile462Val and T3801C at 3'UTR) of CYP1A1 gene in prostate cancer were analyzed in a case-control study of 100 individuals in South Indian population. The estimated relative risk was significantly high for individuals with w1/m1 genotype at 3'UTR of CYP1A1 gene (OR-4.64; 95%CI = 1.51-14.86; P < 0.01) whereas the CYP1A1 Ile/Val genotype (w2/m2) on exon 7 was found to be associated with a decreased risk for prostate cancer (OR-0.17; 95%CI = 0.02-0.89; P=0.03). A Stratified analysis of the genotypes with age of onset and tumor grade showed the w1/m1 genotype to be significantly associated with an early age of onset; however the tumor grades did not have significant association with the variant genotypes. Thus the present study indicates that individuals with the variant w1/m1 genotype exhibit an increased risk while those with w2/m2 genotype exhibit a decreased risk for prostate cancer.
[ "Cytochrome", "p4501A1", "gene", "variants", "as", "susceptibility", "marker", "for", "prostate", "cancer", ".", "CYP1A1", "activates", "environmental", "procarcinogens", "and", "catalyzes", "oxidative", "metabolism", "of", "estrogens", "and", "is", "likely", "to", "play", "an", "important", "role", "in", "the", "etiology", "of", "prostate", "cancer", ".", "To", "evaluate", "this", "phenomenon", ",", "the", "association", "between", "two", "single", "nucleotide", "polymorphisms", "(", "A", "to", "G", "transition", "in", "exon7", "leading", "to", "amino", "acid", "substitution", "Ile462Val", "and", "T3801C", "at", "3'UTR", ")", "of", "CYP1A1", "gene", "in", "prostate", "cancer", "were", "analyzed", "in", "a", "case-control", "study", "of", "100", "individuals", "in", "South", "Indian", "population", ".", "The", "estimated", "relative", "risk", "was", "significantly", "high", "for", "individuals", "with", "w1/m1", "genotype", "at", "3'UTR", "of", "CYP1A1", "gene", "(", "OR-4.64", ";", "95", "%", "CI", "=", "1.51-14.86", ";", "P", "<", "0.01", ")", "whereas", "the", "CYP1A1", "Ile/Val", "genotype", "(", "w2/m2", ")", "on", "exon", "7", "was", "found", "to", "be", "associated", "with", "a", "decreased", "risk", "for", "prostate", "cancer", "(", "OR-0.17", ";", "95", "%", "CI", "=", "0.02-0.89", ";", "P=0.03", ")", ".", "A", "Stratified", "analysis", "of", "the", "genotypes", "with", "age", "of", "onset", "and", "tumor", "grade", "showed", "the", "w1/m1", "genotype", "to", "be", "significantly", "associated", "with", "an", "early", "age", "of", "onset", ";", "however", "the", "tumor", "grades", "did", "not", "have", "significant", "association", "with", "the", "variant", "genotypes", ".", "Thus", "the", "present", "study", "indicates", "that", "individuals", "with", "the", "variant", "w1/m1", "genotype", "exhibit", "an", "increased", "risk", "while", "those", "with", "w2/m2", "genotype", "exhibit", "a", "decreased", "risk", "for", "prostate", "cancer", "." ]
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22051099
Variation in the CXCR1 gene (IL8RA) is not associated with susceptibility to chronic periodontitis. BACKGROUND: The chemokine receptor 1 CXCR-1 (or IL8R-alpha) is a specific receptor for the interleukin 8 (IL-8), which is chemoattractant for neutrophils and has an important role in the inflammatory response. The polymorphism rs2234671 at position Ex2+860G>C of the CXCR1 gene causes a conservative amino acid substitution (S276T). This single nucleotide polymorphism (SNP) seemed to be functional as it was associated with decreased lung cancer risk. Previous studies of our group found association of haplotypes in the IL8 and in the CXCR2 genes with the multifactorial disease chronic periodontitis. In this study we investigated the polymorphism rs2234671 in 395 Brazilian subjects with and without chronic periodontitis. FINDINGS: Similar distribution of the allelic and genotypic frequencies were observed between the groups (p>0.05). CONCLUSIONS: The polymorphism rs2234671 in the CXCR1 gene was not associated with the susceptibility to chronic periodontitis in the studied Brazilian population.
[ "Variation", "in", "the", "CXCR1", "gene", "(", "IL8RA", ")", "is", "not", "associated", "with", "susceptibility", "to", "chronic", "periodontitis", ".", "BACKGROUND", ":", "The", "chemokine", "receptor", "1", "CXCR-1", "(", "or", "IL8R-alpha", ")", "is", "a", "specific", "receptor", "for", "the", "interleukin", "8", "(", "IL-8", ")", ",", "which", "is", "chemoattractant", "for", "neutrophils", "and", "has", "an", "important", "role", "in", "the", "inflammatory", "response", ".", "The", "polymorphism", "rs2234671", "at", "position", "Ex2+860G", ">", "C", "of", "the", "CXCR1", "gene", "causes", "a", "conservative", "amino", "acid", "substitution", "(", "S276T", ")", ".", "This", "single", "nucleotide", "polymorphism", "(", "SNP", ")", "seemed", "to", "be", "functional", "as", "it", "was", "associated", "with", "decreased", "lung", "cancer", "risk", ".", "Previous", "studies", "of", "our", "group", "found", "association", "of", "haplotypes", "in", "the", "IL8", "and", "in", "the", "CXCR2", "genes", "with", "the", "multifactorial", "disease", "chronic", "periodontitis", ".", "In", "this", "study", "we", "investigated", "the", "polymorphism", "rs2234671", "in", "395", "Brazilian", "subjects", "with", "and", "without", "chronic", "periodontitis", ".", "FINDINGS", ":", "Similar", "distribution", "of", "the", "allelic", "and", "genotypic", "frequencies", "were", "observed", "between", "the", "groups", "(", "p", ">", "0.05", ")", ".", "CONCLUSIONS", ":", "The", "polymorphism", "rs2234671", "in", "the", "CXCR1", "gene", "was", "not", "associated", "with", "the", "susceptibility", "to", "chronic", "periodontitis", "in", "the", "studied", "Brazilian", "population", "." ]
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15033202
Nijmegen breakage syndrome in 13% of age-matched Czech children with primary microcephaly. The Nijmegen breakage syndrome is a rare autosomal recessive chromosomal instability disorder characterized by early growth retardation, congenital microcephaly, immunodeficiency, borderline mental development, and a high tendency to lymphoreticular malignancies. Most Nijmegen breakage syndrome patients are of Slavonic origin, and all of them known so far carry a founder homozygous 5 nucleotide deletion in the NBS1 gene. Microcephaly was present in 100% of Nijmegen breakage syndrome patients in a recent large international cooperative study. The frequency of Nijmegen breakage syndrome among children with primary microcephaly was not known. Early correct diagnosis of the syndrome is crucial for appropriate preventive care and therapy. We tested 67 Czech patients of different ages with simple microcephaly for the presence of the most common mutation in the NBS1 gene. Three new Nijmegen breakage syndrome cases were detected in this cohort, representing 4.5% of the cohort. All these newly diagnosed Nijmegen breakage syndrome patients were younger than 10 months at the time of diagnosis. They were all born within a 2.5-year period. Twenty-three of the 67 children in the cohort were born within this 2.5-year period, representing a 13% incidence of Nijmegen breakage syndrome. Frequency of Nijmegen breakage syndrome heterozygotes among infants in the Czech Republic is 1: 130-158 and the birth rate is 90,000 per year, therefore in the time span of 2.5 years, three new Nijmegen breakage syndrome homozygotes are expected to be born. Therefore we assume that by DNA testing of Czech primary microcephalic children it is possible to detect all Nijmegen breakage syndrome patients to be expected. The age at correct diagnosis was lowered from 7.1 years at the time before DNA testing, to well under 1 year of age. All new Nijmegen breakage syndrome patients could receive appropriate preventive care, which should significantly improve their life expectancy and prognosis.
[ "Nijmegen", "breakage", "syndrome", "in", "13", "%", "of", "age-matched", "Czech", "children", "with", "primary", "microcephaly", ".", "The", "Nijmegen", "breakage", "syndrome", "is", "a", "rare", "autosomal", "recessive", "chromosomal", "instability", "disorder", "characterized", "by", "early", "growth", "retardation", ",", "congenital", "microcephaly", ",", "immunodeficiency", ",", "borderline", "mental", "development", ",", "and", "a", "high", "tendency", "to", "lymphoreticular", "malignancies", ".", "Most", "Nijmegen", "breakage", "syndrome", "patients", "are", "of", "Slavonic", "origin", ",", "and", "all", "of", "them", "known", "so", "far", "carry", "a", "founder", "homozygous", "5", "nucleotide", "deletion", "in", "the", "NBS1", "gene", ".", "Microcephaly", "was", "present", "in", "100", "%", "of", "Nijmegen", "breakage", "syndrome", "patients", "in", "a", "recent", "large", "international", "cooperative", "study", ".", "The", "frequency", "of", "Nijmegen", "breakage", "syndrome", "among", "children", "with", "primary", "microcephaly", "was", "not", "known", ".", "Early", "correct", "diagnosis", "of", "the", "syndrome", "is", "crucial", "for", "appropriate", "preventive", "care", "and", "therapy", ".", "We", "tested", "67", "Czech", "patients", "of", "different", "ages", "with", "simple", "microcephaly", "for", "the", "presence", "of", "the", "most", "common", "mutation", "in", "the", "NBS1", "gene", ".", "Three", "new", "Nijmegen", "breakage", "syndrome", "cases", "were", "detected", "in", "this", "cohort", ",", "representing", "4.5", "%", "of", "the", "cohort", ".", "All", "these", "newly", "diagnosed", "Nijmegen", "breakage", "syndrome", "patients", "were", "younger", "than", "10", "months", "at", "the", "time", "of", "diagnosis", ".", "They", "were", "all", "born", "within", "a", "2.5-year", "period", ".", "Twenty-three", "of", "the", "67", "children", "in", "the", "cohort", "were", "born", "within", "this", "2.5-year", "period", ",", "representing", "a", "13", "%", "incidence", "of", "Nijmegen", "breakage", "syndrome", ".", "Frequency", "of", "Nijmegen", "breakage", "syndrome", "heterozygotes", "among", "infants", "in", "the", "Czech", "Republic", "is", "1", ":", "130-158", "and", "the", "birth", "rate", "is", "90,000", "per", "year", ",", "therefore", "in", "the", "time", "span", "of", "2.5", "years", ",", "three", "new", "Nijmegen", "breakage", "syndrome", "homozygotes", "are", "expected", "to", "be", "born", ".", "Therefore", "we", "assume", "that", "by", "DNA", "testing", "of", "Czech", "primary", "microcephalic", "children", "it", "is", "possible", "to", "detect", "all", "Nijmegen", "breakage", "syndrome", "patients", "to", "be", "expected", ".", "The", "age", "at", "correct", "diagnosis", "was", "lowered", "from", "7.1", "years", "at", "the", "time", "before", "DNA", "testing", ",", "to", "well", "under", "1", "year", "of", "age", ".", "All", "new", "Nijmegen", "breakage", "syndrome", "patients", "could", "receive", "appropriate", "preventive", "care", ",", "which", "should", "significantly", "improve", "their", "life", "expectancy", "and", "prognosis", "." ]
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16120104
A single-nucleotide polymorphism in the 5'-untranslated region of the hPER2 gene is associated with diurnal preference. The PERIOD2 (PER2) gene is a key component of the molecular mechanism that generates circadian rhythms in mammals. A missense mutation in the human PER2 gene has previously been linked to advanced sleep phase syndrome (ASPS). We have investigated three other single-nucleotide polymorphisms in the hPER2 gene, one downstream of the transcription start site (C-1228T), one in exon 2 in the 5'-untranslated region (5'-UTR) (C111G), and one missense mutation (G3853A) causing a glycine to glutamine substitution in the predicted protein. Subjects selected from a group of 484 volunteers for extreme morning or evening preference, or intermediate diurnal preference were genotyped with regard to the three polymorphisms (n=35 for each group). Whereas allele frequencies for the other two polymorphisms did not differ significantly between any of the groups, the 111G allele frequency was significantly higher in subjects with extreme morning preference (0.14) than in subjects with extreme evening preference (0.03) (Fisher's exact test, two-sided P value=0.031, odds ratio=5.67). No significant difference in 111G allele frequency was observed between either of these groups and subjects with intermediate diurnal preference. Computer prediction indicated that the C111G polymorphism, which occurs 12 bases upstream from the translation start codon, might alter the secondary structure of the transcript. The PER2 111G allele associates with morning preference and is a potential candidate allele for ASPS.
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17003357
A haplotype-based analysis of the PTPN22 locus in type 1 diabetes. A recent addition to the list of widely confirmed type 1 diabetes risk loci is the PTPN22 gene encoding a lymphoid-specific phosphatase (Lyp). However, evidence supporting a role for PTPN22 in type 1 diabetes derives entirely from the study of just one coding single nucleotide polymorphism, 1858C/T. In the current study, the haplotype structure of the PTPN22 region was determined, and individual haplotypes were tested for association with type 1 diabetes in family-based tests. The 1858T risk allele occurred on only a single haplotype that was strongly associated with type 1 diabetes (P = 7.9 x 10(-5)). After controlling for the effects of this allele, two other haplotypes were observed to be weakly associated with type 1 diabetes (P < 0.05). Sequencing of the coding region of PTPN22 on these haplotypes revealed a novel variant (2250G/C) predicted to result in a nonsynonymous amino acid substitution. Analysis of PTPN22 transcripts from a subject heterozygous for this variant indicated that it interfered with normal mRNA splicing, resulting in a premature termination codon after exon 17. These results support the conclusion that the 1858C/T allele is the major risk variant for type 1 diabetes in the PTPN22 locus, but they suggest that additional infrequent coding variants at PTPN22 may also contribute to type 1 diabetes risk.
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17277899
Polymorphic Alu insertions and the genetic structure of Iberian Basques. Eight Alu sequences (ACE, TPA25, PV92, APO, FXIIIB, D1, A25 and B65) were analyzed in two samples from Navarre and Guipuzcoa provinces (Basque Country, Spain). Alu data for other European, Caucasus and North African populations were compiled from the literature for comparison purposes to assess the genetic relationships of the Basques in a broader geographic context. Results of both MDS plot and AMOVA revealed spatial heterogeneity among these three population clusters clearly defined by geography. On the contrary, no substantial genetic heterogeneity was found between the Basque samples, or between Basques and other Europeans (excluding Caucasus populations). Moreover, the genetic information obtained from Alu data conflicts with hypotheses linking the origin of Basques with populations from North Africa (Berbers) or from the Caucasus region (Georgia). In order to explain the reduced genetic heterogeneity detected by Alu insertions among Basque subpopulations, values of the Wright's F(ST )statistic were estimated for both Alu markers and a set of short tandem repeats (STRs) in terms of two geographical scales: (1) the Basque Country, (2) Europe (including Basques). In the Basque area, estimates of Wahlund's effect for both genetic markers showed no statistical difference between Basque subpopulations. However, when this analysis was performed on a European scale, F(ST) values were significantly higher for Alu insertions than for STR alleles. From these results, we suggest that the spatial heterogeneity of the Basque gene pool identified in previous polymorphism studies is relatively recent and probably caused by a differential process of genetic admixture with non-Basque neighboring populations modulated by the effect of a linguistic barrier to random mating.
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17628794
Manganese superoxide dismutase (Mn-SOD) gene polymorphisms in urolithiasis. Polymorphism in manganese superoxide dismutase gene (Mn-SOD) is a new approach to identify its probable association with urolithiasis. Oxidative stress may be involved in the development of stone formation in the renal system. MnSOD is one of the primary enzymes that directly scavenges potential harmful oxidizing species. A valine (Val) to alanine (Ala) substitution at amino acid 16, occurring in the mitochondrial targeting sequence of the MnSOD gene, has been associated with an increase in urolithiasis risk. This study was conducted to investigate the association of MnSOD gene polymorphism with the risk of urolithiasis. We investigated the MnSOD in 66 stone-forming adults and 72 healthy volunteers. DNA was isolated from peripheral blood and genotyping was performed with PCR-based methods. Then PCR products were cut by BsaW1. Products were run on 3% agarose gel, 246 bp regions were 1-Ala-9, 164 and 82 bp products were determined as 2 Val-9. Chi-square test was used for comparison between patients and controls. In the control group the homozygote Ala allele was significantly higher than in the patient group (P < 0.01). The distribution of Ala/Val and homozygote Val alleles in the patient group was significantly higher than in the control group (P < 0.05). MnSOD genotype determination may provide a tool to identify individuals who are at risk of urolithiasis. This experiment also provides data about antioxidant status and stone formation.
[ "Manganese", "superoxide", "dismutase", "(", "Mn-SOD", ")", "gene", "polymorphisms", "in", "urolithiasis", ".", "Polymorphism", "in", "manganese", "superoxide", "dismutase", "gene", "(", "Mn-SOD", ")", "is", "a", "new", "approach", "to", "identify", "its", "probable", "association", "with", "urolithiasis", ".", "Oxidative", "stress", "may", "be", "involved", "in", "the", "development", "of", "stone", "formation", "in", "the", "renal", "system", ".", "MnSOD", "is", "one", "of", "the", "primary", "enzymes", "that", "directly", "scavenges", "potential", "harmful", "oxidizing", "species", ".", "A", "valine", "(", "Val", ")", "to", "alanine", "(", "Ala", ")", "substitution", "at", "amino", "acid", "16", ",", "occurring", "in", "the", "mitochondrial", "targeting", "sequence", "of", "the", "MnSOD", "gene", ",", "has", "been", "associated", "with", "an", "increase", "in", "urolithiasis", "risk", ".", "This", "study", "was", "conducted", "to", "investigate", "the", "association", "of", "MnSOD", "gene", "polymorphism", "with", "the", "risk", "of", "urolithiasis", ".", "We", "investigated", "the", "MnSOD", "in", "66", "stone-forming", "adults", "and", "72", "healthy", "volunteers", ".", "DNA", "was", "isolated", "from", "peripheral", "blood", "and", "genotyping", "was", "performed", "with", "PCR-based", "methods", ".", "Then", "PCR", "products", "were", "cut", "by", "BsaW1", ".", "Products", "were", "run", "on", "3", "%", "agarose", "gel", ",", "246", "bp", "regions", "were", "1-Ala-9", ",", "164", "and", "82", "bp", "products", "were", "determined", "as", "2", "Val-9", ".", "Chi-square", "test", "was", "used", "for", "comparison", "between", "patients", "and", "controls", ".", "In", "the", "control", "group", "the", "homozygote", "Ala", "allele", "was", "significantly", "higher", "than", "in", "the", "patient", "group", "(", "P", "<", "0.01", ")", ".", "The", "distribution", "of", "Ala/Val", "and", "homozygote", "Val", "alleles", "in", "the", "patient", "group", "was", "significantly", "higher", "than", "in", "the", "control", "group", "(", "P", "<", "0.05", ")", ".", "MnSOD", "genotype", "determination", "may", "provide", "a", "tool", "to", "identify", "individuals", "who", "are", "at", "risk", "of", "urolithiasis", ".", "This", "experiment", "also", "provides", "data", "about", "antioxidant", "status", "and", "stone", "formation", "." ]
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19160446
P2RX7: A bipolar and unipolar disorder candidate susceptibility gene? The chromosomal region 12q24 has been previously implicated by linkage studies of both bipolar disorder and unipolar mood disorder and we have reported two pedigrees segregating both bipolar disorder and Darier's disease that show linkage across this region. The gene P2RX7 is located in this chromosomal region and has been recently reported as a susceptibility gene for bipolar disorder and unipolar depression. The non-synonymous SNP rs2230912 (resulting in amino-acid polymorphism Q460R) showed the strongest association and has been postulated to be pathogenically relevant. We have investigated this gene in a large UK case-control sample (bipolar I disorder N = 687, unipolar recurrent major depression N = 1,036, controls N = 1,204). Neither rs2230912 nor any of 8 other SNPs genotyped across P2RX7 was found to be associated with mood disorder in general, nor specifically with bipolar or unipolar disorder. Further, sequencing of our two chromosome 12-linked bipolar-Darier families showed no evidence of rare variants at P2RX7 that could explain the linkage. Our data do not provide support for rs2230912 or the other polymorphisms studied within the P2RX7 locus, being involved in susceptibility to mood disorders.
[ "P2RX7", ":", "A", "bipolar", "and", "unipolar", "disorder", "candidate", "susceptibility", "gene", "?", "The", "chromosomal", "region", "12q24", "has", "been", "previously", "implicated", "by", "linkage", "studies", "of", "both", "bipolar", "disorder", "and", "unipolar", "mood", "disorder", "and", "we", "have", "reported", "two", "pedigrees", "segregating", "both", "bipolar", "disorder", "and", "Darier", "'s", "disease", "that", "show", "linkage", "across", "this", "region", ".", "The", "gene", "P2RX7", "is", "located", "in", "this", "chromosomal", "region", "and", "has", "been", "recently", "reported", "as", "a", "susceptibility", "gene", "for", "bipolar", "disorder", "and", "unipolar", "depression", ".", "The", "non-synonymous", "SNP", "rs2230912", "(", "resulting", "in", "amino-acid", "polymorphism", "Q460R", ")", "showed", "the", "strongest", "association", "and", "has", "been", "postulated", "to", "be", "pathogenically", "relevant", ".", "We", "have", "investigated", "this", "gene", "in", "a", "large", "UK", "case-control", "sample", "(", "bipolar", "I", "disorder", "N", "=", "687", ",", "unipolar", "recurrent", "major", "depression", "N", "=", "1,036", ",", "controls", "N", "=", "1,204", ")", ".", "Neither", "rs2230912", "nor", "any", "of", "8", "other", "SNPs", "genotyped", "across", "P2RX7", "was", "found", "to", "be", "associated", "with", "mood", "disorder", "in", "general", ",", "nor", "specifically", "with", "bipolar", "or", "unipolar", "disorder", ".", "Further", ",", "sequencing", "of", "our", "two", "chromosome", "12-linked", "bipolar-Darier", "families", "showed", "no", "evidence", "of", "rare", "variants", "at", "P2RX7", "that", "could", "explain", "the", "linkage", ".", "Our", "data", "do", "not", "provide", "support", "for", "rs2230912", "or", "the", "other", "polymorphisms", "studied", "within", "the", "P2RX7", "locus", ",", "being", "involved", "in", "susceptibility", "to", "mood", "disorders", "." ]
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19549709
Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. BACKGROUND: Treatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. RAD001, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown phase I efficacy in NSCLC. METHODS: Stage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one platinum based (stratum 1) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (stratum 2), received RAD001 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. RESULTS: Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. CONCLUSIONS: RAD001 10 mg/day was well tolerated, showing modest clinical activity in pretreated NSCLC. Evaluation of RAD001 plus standard therapy for metastatic NSCLC continues.
[ "Efficacy", "of", "everolimus", "(", "RAD001", ")", "in", "patients", "with", "advanced", "NSCLC", "previously", "treated", "with", "chemotherapy", "alone", "or", "with", "chemotherapy", "and", "EGFR", "inhibitors", ".", "BACKGROUND", ":", "Treatment", "options", "are", "scarce", "in", "pretreated", "advanced", "non-small-cell", "lung", "cancer", "(", "NSCLC", ")", "patients", ".", "RAD001", ",", "an", "oral", "inhibitor", "of", "the", "mammalian", "target", "of", "rapamycin", "(", "mTOR", ")", ",", "has", "shown", "phase", "I", "efficacy", "in", "NSCLC", ".", "METHODS", ":", "Stage", "IIIb", "or", "IV", "NSCLC", "patients", ",", "with", "two", "or", "fewer", "prior", "chemotherapy", "regimens", ",", "one", "platinum", "based", "(", "stratum", "1", ")", "or", "both", "chemotherapy", "and", "epidermal", "growth", "factor", "receptor", "tyrosine", "kinase", "inhibitors", "(", "stratum", "2", ")", ",", "received", "RAD001", "10", "mg/day", "until", "progression", "or", "unacceptable", "toxicity", ".", "Primary", "objective", "was", "overall", "response", "rate", "(", "ORR", ")", ".", "Analyses", "of", "markers", "associated", "with", "the", "mTOR", "pathway", "were", "carried", "out", "on", "archival", "tumor", "from", "a", "subgroup", "using", "immunohistochemistry", "(", "IHC", ")", "and", "direct", "mutation", "sequencing", ".", "RESULTS", ":", "Eighty-five", "patients", "were", "enrolled", ",", "42", "in", "stratum", "1", "and", "43", "in", "stratum", ".", "ORR", "was", "4.7", "%", "(", "7.1", "%", "stratum", "1", ";", "2.3", "%", "stratum", "2", ")", ".", "Overall", "disease", "control", "rate", "was", "47.1", "%", ".", "Median", "progression-free", "survivals", "(", "PFSs", ")", "were", "2.6", "(", "stratum", "1", ")", "and", "2.7", "months", "(", "stratum", "2", ")", ".", "Common", ">", "or", "=grade", "3", "events", "were", "fatigue", ",", "dyspnea", ",", "stomatitis", ",", "anemia", ",", "and", "thrombocytopenia", ".", "Pneumonitis", ",", "probably", "or", "possibly", "related", ",", "mainly", "grade", "1/2", ",", "occurred", "in", "25", "%", ".", "Cox", "regression", "analysis", "of", "IHC", "scores", "found", "that", "only", "phospho", "AKT", "(", "pAKT", ")", "was", "a", "significant", "independent", "predictor", "of", "worse", "PFS", ".", "CONCLUSIONS", ":", "RAD001", "10", "mg/day", "was", "well", "tolerated", ",", "showing", "modest", "clinical", "activity", "in", "pretreated", "NSCLC", ".", "Evaluation", "of", "RAD001", "plus", "standard", "therapy", "for", "metastatic", "NSCLC", "continues", "." ]
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19891556
Clopidogrel pharmacogenomics and risk of inadequate platelet inhibition: US FDA recommendations. Antiplatelet therapy with clopidogrel is the current standard of care for coronary artery disease patients undergoing a percutaneous coronary intervention. However, approximately 25% of patients experience a subtherapeutic antiplatelet response. Clopidogrel is a prodrug that undergoes hepatic biotransformation by CYP2C19 into its active metabolite. Several studies have reported that, compared with wild-type individuals, CYP2C19 variant allele carriers exhibit a significantly lower capacity to metabolize clopidogrel into its active metabolite and inhibit platelet activation, and are therefore at significantly higher risk of adverse cardiovascular events. Consequently, the US FDA has recently changed clopidogrel's prescribing information to highlight the impact of CYP2C19 genotype on clopidogrel pharmacokinetics, pharmacodynamics and clinical response. Future studies remain necessary to develop effective personalized therapeutic strategies for CYP2C19 variant allele carriers and other individuals at risk for clopidogrel nonresponsiveness.
[ "Clopidogrel", "pharmacogenomics", "and", "risk", "of", "inadequate", "platelet", "inhibition", ":", "US", "FDA", "recommendations", ".", "Antiplatelet", "therapy", "with", "clopidogrel", "is", "the", "current", "standard", "of", "care", "for", "coronary", "artery", "disease", "patients", "undergoing", "a", "percutaneous", "coronary", "intervention", ".", "However", ",", "approximately", "25", "%", "of", "patients", "experience", "a", "subtherapeutic", "antiplatelet", "response", ".", "Clopidogrel", "is", "a", "prodrug", "that", "undergoes", "hepatic", "biotransformation", "by", "CYP2C19", "into", "its", "active", "metabolite", ".", "Several", "studies", "have", "reported", "that", ",", "compared", "with", "wild-type", "individuals", ",", "CYP2C19", "variant", "allele", "carriers", "exhibit", "a", "significantly", "lower", "capacity", "to", "metabolize", "clopidogrel", "into", "its", "active", "metabolite", "and", "inhibit", "platelet", "activation", ",", "and", "are", "therefore", "at", "significantly", "higher", "risk", "of", "adverse", "cardiovascular", "events", ".", "Consequently", ",", "the", "US", "FDA", "has", "recently", "changed", "clopidogrel", "'s", "prescribing", "information", "to", "highlight", "the", "impact", "of", "CYP2C19", "genotype", "on", "clopidogrel", "pharmacokinetics", ",", "pharmacodynamics", "and", "clinical", "response", ".", "Future", "studies", "remain", "necessary", "to", "develop", "effective", "personalized", "therapeutic", "strategies", "for", "CYP2C19", "variant", "allele", "carriers", "and", "other", "individuals", "at", "risk", "for", "clopidogrel", "nonresponsiveness", "." ]
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20367983
Mutation analysis in a Chinese family with multiple endocrine neoplasia type 1. BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant cancer syndrome which is caused by germline mutations of the tumor suppressor gene MEN1. This study aimed to identify mutations in a Chinese pedigree with MEN1. METHODS: A large Chinese family with MEN1 was collected. All of the coded regions and their adjacent sequences of the MEN1 gene were amplified and sequenced. RESULTS: In this family, a heterozygous cytosine insertion in exon 10 (c.1546_1547insC) inducing a frame shift mutation of MEN1 was found in the proband and the other two suffering members of his family. This mutation was linked to a novel single nucleotide polymorphism (SNP) in intron 3 (IVS3 + 18C > T). CONCLUSIONS: The mutation in exon 10 of MEN1 gene might induce development of parathyroid hyperplasia and pituitary adenoma and cosegregate with MEN1 syndrome. The significance of the new found IVS3 + 18C > T of MEN1 needs a further investigation.
[ "Mutation", "analysis", "in", "a", "Chinese", "family", "with", "multiple", "endocrine", "neoplasia", "type", "1", ".", "BACKGROUND", ":", "Multiple", "endocrine", "neoplasia", "type", "1", "(", "MEN1", ")", "is", "an", "autosomal", "dominant", "cancer", "syndrome", "which", "is", "caused", "by", "germline", "mutations", "of", "the", "tumor", "suppressor", "gene", "MEN1", ".", "This", "study", "aimed", "to", "identify", "mutations", "in", "a", "Chinese", "pedigree", "with", "MEN1", ".", "METHODS", ":", "A", "large", "Chinese", "family", "with", "MEN1", "was", "collected", ".", "All", "of", "the", "coded", "regions", "and", "their", "adjacent", "sequences", "of", "the", "MEN1", "gene", "were", "amplified", "and", "sequenced", ".", "RESULTS", ":", "In", "this", "family", ",", "a", "heterozygous", "cytosine", "insertion", "in", "exon", "10", "(", "c.1546_1547insC", ")", "inducing", "a", "frame", "shift", "mutation", "of", "MEN1", "was", "found", "in", "the", "proband", "and", "the", "other", "two", "suffering", "members", "of", "his", "family", ".", "This", "mutation", "was", "linked", "to", "a", "novel", "single", "nucleotide", "polymorphism", "(", "SNP", ")", "in", "intron", "3", "(", "IVS3", "+", "18C", ">", "T", ")", ".", "CONCLUSIONS", ":", "The", "mutation", "in", "exon", "10", "of", "MEN1", "gene", "might", "induce", "development", "of", "parathyroid", "hyperplasia", "and", "pituitary", "adenoma", "and", "cosegregate", "with", "MEN1", "syndrome", ".", "The", "significance", "of", "the", "new", "found", "IVS3", "+", "18C", ">", "T", "of", "MEN1", "needs", "a", "further", "investigation", "." ]
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22180037
Genetic polymorphism of the glutathione-S-transferase P1 gene (GSTP1) and susceptibility to prostate cancer in the Kashmiri population. Glutathione-S-transferase P1 (GSTP1) is a critical enzyme of the phase II detoxification pathway. One of the common functional polymorphisms of GSTP1 is A > G at nucleotide 313, which results in an amino acid substitution (Ile105Val) at the substrate binding site of GSTP1 and reduces catalytic activity of GSTP1. To investigate the GSTP1 Ile105Val genotype frequency in prostate cancer cases in the Kashmiri population, we designed a case-control study, in which 50 prostate cancer cases and 45 benign prostate hyperplasia cases were studied for GSTP1 Ile105Val polymorphism, compared to 80 controls taken from the general population, employing the PCR-RFLP technique. We found the frequency of the three different genotypes of GSTP1 Ile105Val in our ethnic Kashmir population, i.e., Ile/Ile, Ile/Val and Val/Val, to be 52.4, 33.3 and 14.3% among prostate cancer cases, 48.5, 37.5 and 14% among benign prostate hyperplasia cases and 73.8, 21.3 and 5% in the control population, respectively. There was a significant association between the GSTP1 Ile/Val genotype and the advanced age group among the cases. We conclude that GSTP1 Ile/Val polymorphism is involved in the risk of prostate cancer development in our population.
[ "Genetic", "polymorphism", "of", "the", "glutathione-S-transferase", "P1", "gene", "(", "GSTP1", ")", "and", "susceptibility", "to", "prostate", "cancer", "in", "the", "Kashmiri", "population", ".", "Glutathione-S-transferase", "P1", "(", "GSTP1", ")", "is", "a", "critical", "enzyme", "of", "the", "phase", "II", "detoxification", "pathway", ".", "One", "of", "the", "common", "functional", "polymorphisms", "of", "GSTP1", "is", "A", ">", "G", "at", "nucleotide", "313", ",", "which", "results", "in", "an", "amino", "acid", "substitution", "(", "Ile105Val", ")", "at", "the", "substrate", "binding", "site", "of", "GSTP1", "and", "reduces", "catalytic", "activity", "of", "GSTP1", ".", "To", "investigate", "the", "GSTP1", "Ile105Val", "genotype", "frequency", "in", "prostate", "cancer", "cases", "in", "the", "Kashmiri", "population", ",", "we", "designed", "a", "case-control", "study", ",", "in", "which", "50", "prostate", "cancer", "cases", "and", "45", "benign", "prostate", "hyperplasia", "cases", "were", "studied", "for", "GSTP1", "Ile105Val", "polymorphism", ",", "compared", "to", "80", "controls", "taken", "from", "the", "general", "population", ",", "employing", "the", "PCR-RFLP", "technique", ".", "We", "found", "the", "frequency", "of", "the", "three", "different", "genotypes", "of", "GSTP1", "Ile105Val", "in", "our", "ethnic", "Kashmir", "population", ",", "i.e.", ",", "Ile/Ile", ",", "Ile/Val", "and", "Val/Val", ",", "to", "be", "52.4", ",", "33.3", "and", "14.3", "%", "among", "prostate", "cancer", "cases", ",", "48.5", ",", "37.5", "and", "14", "%", "among", "benign", "prostate", "hyperplasia", "cases", "and", "73.8", ",", "21.3", "and", "5", "%", "in", "the", "control", "population", ",", "respectively", ".", "There", "was", "a", "significant", "association", "between", "the", "GSTP1", "Ile/Val", "genotype", "and", "the", "advanced", "age", "group", "among", "the", "cases", ".", "We", "conclude", "that", "GSTP1", "Ile/Val", "polymorphism", "is", "involved", "in", "the", "risk", "of", "prostate", "cancer", "development", "in", "our", "population", "." ]
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26270232
Serum levels of chemokines CCL4 and CCL5 in cirrhotic patients indicate the presence of hepatocellular carcinoma. BACKGROUND: Most hepatocellular carcinomas (HCCs) are diagnosed at an advanced stage. The prognostic value of serum tumour markers alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) is limited. The aim of our study is to evaluate the diagnostic value of serum growth factors, apoptotic and inflammatory mediators of cirrhotic patients with and without HCC. METHODS: Serum samples were collected from cirrhotic potential liver transplant patients (LTx) with (n=61) and without HCC (n=78) as well as from healthy controls (HCs; n=39). Serum concentrations of CRP, neopterin and IL-6 as markers of inflammation and thrombopoietin (TPO), GCSF, FGF basic and VEGF, HMGB1, CK-18 (M65) and CK18 fragment (M30) and a panel of proinflammatory chemokines (CCL2, CCL3, CCL4, CCL5, CXCL5 and IL-8) were measured. Chi square, Fisher exact, Mann-Whitney U-tests, ROC curve analysis and forward stepwise logistic regression analyses were applied. RESULTS: Patients with HCC had higher serum TPO and chemokines (P <0.001 for TPO, CCL4, CCL5 and CXCL5) and lower CCL2 (P=0.008) levels than cirrhotic patients without HCC. Multivariate forward stepwise regression analysis for significant parameters showed that among the studied parameters CCL4 and CCL5 (P=0.001) are diagnostic markers of HCC. Serum levels of TPO and chemokines were lower, whereas M30 was significantly higher in cirrhotic patients than in HCs. CONCLUSIONS: High serum levels of inflammatory chemokines such as CCL4 and CCL5 in the serum of cirrhotic patients indicate the presence of HCC.
[ "Serum", "levels", "of", "chemokines", "CCL4", "and", "CCL5", "in", "cirrhotic", "patients", "indicate", "the", "presence", "of", "hepatocellular", "carcinoma", ".", "BACKGROUND", ":", "Most", "hepatocellular", "carcinomas", "(", "HCCs", ")", "are", "diagnosed", "at", "an", "advanced", "stage", ".", "The", "prognostic", "value", "of", "serum", "tumour", "markers", "alpha-fetoprotein", "(", "AFP", ")", "and", "des-gamma-carboxy", "prothrombin", "(", "DCP", ")", "is", "limited", ".", "The", "aim", "of", "our", "study", "is", "to", "evaluate", "the", "diagnostic", "value", "of", "serum", "growth", "factors", ",", "apoptotic", "and", "inflammatory", "mediators", "of", "cirrhotic", "patients", "with", "and", "without", "HCC", ".", "METHODS", ":", "Serum", "samples", "were", "collected", "from", "cirrhotic", "potential", "liver", "transplant", "patients", "(", "LTx", ")", "with", "(", "n=61", ")", "and", "without", "HCC", "(", "n=78", ")", "as", "well", "as", "from", "healthy", "controls", "(", "HCs", ";", "n=39", ")", ".", "Serum", "concentrations", "of", "CRP", ",", "neopterin", "and", "IL-6", "as", "markers", "of", "inflammation", "and", "thrombopoietin", "(", "TPO", ")", ",", "GCSF", ",", "FGF", "basic", "and", "VEGF", ",", "HMGB1", ",", "CK-18", "(", "M65", ")", "and", "CK18", "fragment", "(", "M30", ")", "and", "a", "panel", "of", "proinflammatory", "chemokines", "(", "CCL2", ",", "CCL3", ",", "CCL4", ",", "CCL5", ",", "CXCL5", "and", "IL-8", ")", "were", "measured", ".", "Chi", "square", ",", "Fisher", "exact", ",", "Mann-Whitney", "U-tests", ",", "ROC", "curve", "analysis", "and", "forward", "stepwise", "logistic", "regression", "analyses", "were", "applied", ".", "RESULTS", ":", "Patients", "with", "HCC", "had", "higher", "serum", "TPO", "and", "chemokines", "(", "P", "<", "0.001", "for", "TPO", ",", "CCL4", ",", "CCL5", "and", "CXCL5", ")", "and", "lower", "CCL2", "(", "P=0.008", ")", "levels", "than", "cirrhotic", "patients", "without", "HCC", ".", "Multivariate", "forward", "stepwise", "regression", "analysis", "for", "significant", "parameters", "showed", "that", "among", "the", "studied", "parameters", "CCL4", "and", "CCL5", "(", "P=0.001", ")", "are", "diagnostic", "markers", "of", "HCC", ".", "Serum", "levels", "of", "TPO", "and", "chemokines", "were", "lower", ",", "whereas", "M30", "was", "significantly", "higher", "in", "cirrhotic", "patients", "than", "in", "HCs", ".", "CONCLUSIONS", ":", "High", "serum", "levels", "of", "inflammatory", "chemokines", "such", "as", "CCL4", "and", "CCL5", "in", "the", "serum", "of", "cirrhotic", "patients", "indicate", "the", "presence", "of", "HCC", "." ]
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16288199
The promoter of inducible nitric oxide synthase implicated in glaucoma based on genetic analysis and nuclear factor binding. PURPOSE: Nitric oxide has many beneficial functions in the human body at the right amounts, but it can also be hazardous if it is produced in amounts more than needed and has therefore been studied in relation to several neurological and non-neurological disorders. In vitro and in vivo studies demonstrate a connection between the inducible form of Nitric Oxide Synthase, iNOS, and the neuropathological disorder glaucoma, one of the major causes of blindness in the world. In this study, we sought to establish the genetic association between iNOS and primary open angle glaucoma, POAG, and to find the functional element(s) connected with the pathogenesis of the disease. METHODS: Two microsatellites, 1 insertion/deletion, and 8 single nucleotide polymorphisms (SNPs) in the regulatory region of iNOS were genotyped in 200 POAG patients and 200 age-matched controls. Also, the CCTTT-microsatellite was examined for its protein-binding capability in an electrophoretic mobility shift assay, EMSA. RESULTS: There was a significant difference in allele distribution of the CCTTT-microsatellite, between patients and controls. (CCTTT)14, which has been reported to have a higher activity in a reporter-construct, was significantly more abundant in POAG patients, while (CCTTT)10 and (CCTTT)13 were less common. In EMSA, the (CCTTT)14 allele exhibited specific binding of nuclear proteins. CONCLUSIONS: These results, together with other studies on this gene and the CCTTT-microsatellite, establish, for the first time, a genetic association of iNOS with POAG and suggest a regulatory function for the microsatellite.
[ "The", "promoter", "of", "inducible", "nitric", "oxide", "synthase", "implicated", "in", "glaucoma", "based", "on", "genetic", "analysis", "and", "nuclear", "factor", "binding", ".", "PURPOSE", ":", "Nitric", "oxide", "has", "many", "beneficial", "functions", "in", "the", "human", "body", "at", "the", "right", "amounts", ",", "but", "it", "can", "also", "be", "hazardous", "if", "it", "is", "produced", "in", "amounts", "more", "than", "needed", "and", "has", "therefore", "been", "studied", "in", "relation", "to", "several", "neurological", "and", "non-neurological", "disorders", ".", "In", "vitro", "and", "in", "vivo", "studies", "demonstrate", "a", "connection", "between", "the", "inducible", "form", "of", "Nitric", "Oxide", "Synthase", ",", "iNOS", ",", "and", "the", "neuropathological", "disorder", "glaucoma", ",", "one", "of", "the", "major", "causes", "of", "blindness", "in", "the", "world", ".", "In", "this", "study", ",", "we", "sought", "to", "establish", "the", "genetic", "association", "between", "iNOS", "and", "primary", "open", "angle", "glaucoma", ",", "POAG", ",", "and", "to", "find", "the", "functional", "element", "(", "s", ")", "connected", "with", "the", "pathogenesis", "of", "the", "disease", ".", "METHODS", ":", "Two", "microsatellites", ",", "1", "insertion/deletion", ",", "and", "8", "single", "nucleotide", "polymorphisms", "(", "SNPs", ")", "in", "the", "regulatory", "region", "of", "iNOS", "were", "genotyped", "in", "200", "POAG", "patients", "and", "200", "age-matched", "controls", ".", "Also", ",", "the", "CCTTT-microsatellite", "was", "examined", "for", "its", "protein-binding", "capability", "in", "an", "electrophoretic", "mobility", "shift", "assay", ",", "EMSA", ".", "RESULTS", ":", "There", "was", "a", "significant", "difference", "in", "allele", "distribution", "of", "the", "CCTTT-microsatellite", ",", "between", "patients", "and", "controls", ".", "(", "CCTTT", ")", "14", ",", "which", "has", "been", "reported", "to", "have", "a", "higher", "activity", "in", "a", "reporter-construct", ",", "was", "significantly", "more", "abundant", "in", "POAG", "patients", ",", "while", "(", "CCTTT", ")", "10", "and", "(", "CCTTT", ")", "13", "were", "less", "common", ".", "In", "EMSA", ",", "the", "(", "CCTTT", ")", "14", "allele", "exhibited", "specific", "binding", "of", "nuclear", "proteins", ".", "CONCLUSIONS", ":", "These", "results", ",", "together", "with", "other", "studies", "on", "this", "gene", "and", "the", "CCTTT-microsatellite", ",", "establish", ",", "for", "the", "first", "time", ",", "a", "genetic", "association", "of", "iNOS", "with", "POAG", "and", "suggest", "a", "regulatory", "function", "for", "the", "microsatellite", "." ]
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16391785
Homozygous deletion and reduced expression of the DOCK8 gene in human lung cancer. A homozygous deletion of the DOCK8 (dedicator of cytokinesis 8) locus at chromosome 9p24 was found in a lung cancer cell line by array-CGH analysis. Cloning of the full-length DOCK8 cDNA led us to define that the DOCK8 gene encodes a protein consisting of 2,099 amino acids. DOCK8 was expressed in a variety of human organs, including the lungs, and was also expressed in type II alveolar, bronchiolar epithelial and bronchial epithelial cells, which are considered as being progenitors for lung cancer cells. DOCK8 expression was reduced in 62/71 (87%) primary lung cancers compared with normal lung tissue, and the reduction occurred irrespective of the histological type of lung cancer. 5-Aza-2'-deoxy-cytidine and/or Trichostatin A treatments induced DOCK8 expression in lung cancer cell lines with reduced DOCK8 expression. Therefore, epigenetic mechanisms, including DNA methylation and histone deacetylation, were indicated to be involved in DOCK8 down-regulation in lung cancer cells. Further screening revealed homozygous deletions of the DOCK8 gene in a gastric and a breast cancer cell line. DOCK family proteins have been shown to play roles in regulation of migration, morphology, adhesion and growth of cells. Thus, the present results suggest that genetic and epigenetic inactivation of DOCK8 is involved in the development and/or progression of lung and other cancers by disturbing such regulations.
[ "Homozygous", "deletion", "and", "reduced", "expression", "of", "the", "DOCK8", "gene", "in", "human", "lung", "cancer", ".", "A", "homozygous", "deletion", "of", "the", "DOCK8", "(", "dedicator", "of", "cytokinesis", "8", ")", "locus", "at", "chromosome", "9p24", "was", "found", "in", "a", "lung", "cancer", "cell", "line", "by", "array-CGH", "analysis", ".", "Cloning", "of", "the", "full-length", "DOCK8", "cDNA", "led", "us", "to", "define", "that", "the", "DOCK8", "gene", "encodes", "a", "protein", "consisting", "of", "2,099", "amino", "acids", ".", "DOCK8", "was", "expressed", "in", "a", "variety", "of", "human", "organs", ",", "including", "the", "lungs", ",", "and", "was", "also", "expressed", "in", "type", "II", "alveolar", ",", "bronchiolar", "epithelial", "and", "bronchial", "epithelial", "cells", ",", "which", "are", "considered", "as", "being", "progenitors", "for", "lung", "cancer", "cells", ".", "DOCK8", "expression", "was", "reduced", "in", "62/71", "(", "87", "%", ")", "primary", "lung", "cancers", "compared", "with", "normal", "lung", "tissue", ",", "and", "the", "reduction", "occurred", "irrespective", "of", "the", "histological", "type", "of", "lung", "cancer", ".", "5-Aza-2'-deoxy-cytidine", "and/or", "Trichostatin", "A", "treatments", "induced", "DOCK8", "expression", "in", "lung", "cancer", "cell", "lines", "with", "reduced", "DOCK8", "expression", ".", "Therefore", ",", "epigenetic", "mechanisms", ",", "including", "DNA", "methylation", "and", "histone", "deacetylation", ",", "were", "indicated", "to", "be", "involved", "in", "DOCK8", "down-regulation", "in", "lung", "cancer", "cells", ".", "Further", "screening", "revealed", "homozygous", "deletions", "of", "the", "DOCK8", "gene", "in", "a", "gastric", "and", "a", "breast", "cancer", "cell", "line", ".", "DOCK", "family", "proteins", "have", "been", "shown", "to", "play", "roles", "in", "regulation", "of", "migration", ",", "morphology", ",", "adhesion", "and", "growth", "of", "cells", ".", "Thus", ",", "the", "present", "results", "suggest", "that", "genetic", "and", "epigenetic", "inactivation", "of", "DOCK8", "is", "involved", "in", "the", "development", "and/or", "progression", "of", "lung", "and", "other", "cancers", "by", "disturbing", "such", "regulations", "." ]
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17250663
A novel mutation at the DFNA36 hearing loss locus reveals a critical function and potential genotype-phenotype correlation for amino acid-572 of TMC1. We ascertained a North American Caucasian family (LMG248) segregating autosomal dominant, non-syndromic, post-lingual, progressive sensorineural hearing loss. The hearing loss begins in the second decade of life and initially affects high frequencies. It progresses to profound deafness at all frequencies by the fourth or fifth decade. The phenotype co-segregates with short-tandem repeat markers flanking the TMC1 gene at the DFNA36 locus on chromosome 9q31-q21. The affected individuals carry a novel missense substitution, p.D572H (c.G1714C), of the TMC1 gene. This mutation is at the same nucleotide and amino acid position as the only other reported DFNA36 mutation, p.D572N (c.G1714A). Our observations implicate a critical function for amino acid-572 for wild-type TMC1 function or the pathogenesis of DFNA36 hearing loss. The slower progression of hearing loss associated with p.D572H, in comparison with that caused by p.D572N, may reflect a correlation of DFNA36 phenotype with TMC1 genotype.
[ "A", "novel", "mutation", "at", "the", "DFNA36", "hearing", "loss", "locus", "reveals", "a", "critical", "function", "and", "potential", "genotype-phenotype", "correlation", "for", "amino", "acid-572", "of", "TMC1", ".", "We", "ascertained", "a", "North", "American", "Caucasian", "family", "(", "LMG248", ")", "segregating", "autosomal", "dominant", ",", "non-syndromic", ",", "post-lingual", ",", "progressive", "sensorineural", "hearing", "loss", ".", "The", "hearing", "loss", "begins", "in", "the", "second", "decade", "of", "life", "and", "initially", "affects", "high", "frequencies", ".", "It", "progresses", "to", "profound", "deafness", "at", "all", "frequencies", "by", "the", "fourth", "or", "fifth", "decade", ".", "The", "phenotype", "co-segregates", "with", "short-tandem", "repeat", "markers", "flanking", "the", "TMC1", "gene", "at", "the", "DFNA36", "locus", "on", "chromosome", "9q31-q21", ".", "The", "affected", "individuals", "carry", "a", "novel", "missense", "substitution", ",", "p.D572H", "(", "c.G1714C", ")", ",", "of", "the", "TMC1", "gene", ".", "This", "mutation", "is", "at", "the", "same", "nucleotide", "and", "amino", "acid", "position", "as", "the", "only", "other", "reported", "DFNA36", "mutation", ",", "p.D572N", "(", "c.G1714A", ")", ".", "Our", "observations", "implicate", "a", "critical", "function", "for", "amino", "acid-572", "for", "wild-type", "TMC1", "function", "or", "the", "pathogenesis", "of", "DFNA36", "hearing", "loss", ".", "The", "slower", "progression", "of", "hearing", "loss", "associated", "with", "p.D572H", ",", "in", "comparison", "with", "that", "caused", "by", "p.D572N", ",", "may", "reflect", "a", "correlation", "of", "DFNA36", "phenotype", "with", "TMC1", "genotype", "." ]
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17951029
Focal dermal hypoplasia resulting from a new nonsense mutation, p.E300X, in the PORCN gene. BACKGROUND: Focal dermal hypoplasia (FDH) (OMIM 305600) is an X-linked dominant disorder of ecto-mesodermal development. Also known as Goltz syndrome, FDH presents with characteristic linear streaks of hypoplastic dermis and variable abnormalities of bone, nails, hair, limbs, teeth and eyes. The molecular basis of FDH involves mutations in the PORCN gene, which encodes an enzyme that allows membrane targeting and secretion of several Wnt proteins critical for normal tissue development. OBJECTIVES: To investigate the molecular basis of FDH in a 2-year-old Thai girl who presented at birth with depressed, pale linear scars on the trunk and limbs, sparse brittle hair, syndactyly of the right middle and ring fingers, dental caries and radiological features of osteopathia striata. METHODS: Sequencing of genomic DNA from the affected individual and both parents to search for pathogenic mutations in PORCN gene. RESULTS: DNA sequencing disclosed a heterozygous G>T substitution at nucleotide c.898 within exon 10 (NM_203475.1), converting a glutamic acid residue (GAA) to a premature termination codon (TAA). This mutation, designated p.E300X, was not detected in DNA from either parent or in 100 control chromosomes. CONCLUSION: Identification of this new de novo nonsense mutation confirms the diagnosis of FDH in this child and highlights the clinical importance of PORCN and Wnt signalling pathways in embryogenesis.
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19110214
A recessive skeletal dysplasia, SEMD aggrecan type, results from a missense mutation affecting the C-type lectin domain of aggrecan. Analysis of a nuclear family with three affected offspring identified an autosomal-recessive form of spondyloepimetaphyseal dysplasia characterized by severe short stature and a unique constellation of radiographic findings. Homozygosity for a haplotype that was identical by descent between two of the affected individuals identified a locus for the disease gene within a 17.4 Mb interval on chromosome 15, a region containing 296 genes. These genes were assessed and ranked by cartilage selectivity with whole-genome microarray data, revealing only two genes, encoding aggrecan and chondroitin sulfate proteoglycan 4, that were selectively expressed in cartilage. Sequence analysis of aggrecan complementary DNA from an affected individual revealed homozygosity for a missense mutation (c.6799G --> A) that predicts a p.D2267N amino acid substitution in the C-type lectin domain within the G3 domain of aggrecan. The D2267 residue is predicted to coordinate binding of a calcium ion, which influences the conformational binding loops of the C-type lectin domain that mediate interactions with tenascins and other extracellular-matrix proteins. Expression of the normal and mutant G3 domains in mammalian cells showed that the mutation created a functional N-glycosylation site but did not adversely affect protein trafficking and secretion. Surface-plasmon-resonance studies showed that the mutation influenced the binding and kinetics of the interactions between the aggrecan G3 domain and tenascin-C. These findings identify an autosomal-recessive skeletal dysplasia and a significant role for the aggrecan C-type lectin domain in regulating endochondral ossification and, thereby, height.
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21666969
Roles of G1359A polymorphism of the cannabinoid receptor gene (CNR1) on weight loss and adipocytokines after a hypocaloric diet. BACKGROUND: A intragenic biallelic polymorphism (1359 G/A) of the CB1 gene resulting in the substitution of the G to A at nucleotide position 1359 in codon 435 (Thr), was reported as a common polymorphism in Caucasian populations. Intervention studies with this polymorphism have not been realized. OBJECTIVE: We decided to investigate the role of the polymorphism (G1359A) of CB1 receptor gene on adipocytokines response and weight loss secondary to a lifestyle modification (Mediterranean hypocaloric diet and exercise) in obese patients. DESIGN: A population of 94 patients with obesity was analyzed. Before and after 3 months on a hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake and a biochemical analysis were performed. The statistical analysis was performed for the combined G1359A and A1359A as a group and wild type G1359G as second group, with a dominant model. Results: Forty seven patients (50%) had the genotype G1359G (wild type group) and 47 (50%) patients G1359A (41 patients, 43.6%) or A1359A (6 patients, 6.4%) (mutant type group) had the genotype. In wild and mutant type groups, weight, body mass index, fat mass, waist circumference and systolic blood pressure decreased. In mutant type group, resistin (4.15 1.7 ng/ml vs. 3.90 2.1 ng/ml: P < 0.05), leptin (78.4 69 ng/ml vs 66.2 32 ng/ml: P < 0.05) and IL-6 (1.40 1.9 pg/ml vs 0.81 1.5 pg/ml: P < 0.05) levels decreased after dietary treatment. CONCLUSION: The novel finding of this study is the association of the mutant allele (A1359) with a decrease of resistin, leptin and interleukin-6 secondary to weight loss.
[ "Roles", "of", "G1359A", "polymorphism", "of", "the", "cannabinoid", "receptor", "gene", "(", "CNR1", ")", "on", "weight", "loss", "and", "adipocytokines", "after", "a", "hypocaloric", "diet", ".", "BACKGROUND", ":", "A", "intragenic", "biallelic", "polymorphism", "(", "1359", "G/A", ")", "of", "the", "CB1", "gene", "resulting", "in", "the", "substitution", "of", "the", "G", "to", "A", "at", "nucleotide", "position", "1359", "in", "codon", "435", "(", "Thr", ")", ",", "was", "reported", "as", "a", "common", "polymorphism", "in", "Caucasian", "populations", ".", "Intervention", "studies", "with", "this", "polymorphism", "have", "not", "been", "realized", ".", "OBJECTIVE", ":", "We", "decided", "to", "investigate", "the", "role", "of", "the", "polymorphism", "(", "G1359A", ")", "of", "CB1", "receptor", "gene", "on", "adipocytokines", "response", "and", "weight", "loss", "secondary", "to", "a", "lifestyle", "modification", "(", "Mediterranean", "hypocaloric", "diet", "and", "exercise", ")", "in", "obese", "patients", ".", "DESIGN", ":", "A", "population", "of", "94", "patients", "with", "obesity", "was", "analyzed", ".", "Before", "and", "after", "3", "months", "on", "a", "hypocaloric", "diet", ",", "an", "anthropometric", "evaluation", ",", "an", "assessment", "of", "nutritional", "intake", "and", "a", "biochemical", "analysis", "were", "performed", ".", "The", "statistical", "analysis", "was", "performed", "for", "the", "combined", "G1359A", "and", "A1359A", "as", "a", "group", "and", "wild", "type", "G1359G", "as", "second", "group", ",", "with", "a", "dominant", "model", ".", "Results", ":", "Forty", "seven", "patients", "(", "50", "%", ")", "had", "the", "genotype", "G1359G", "(", "wild", "type", "group", ")", "and", "47", "(", "50", "%", ")", "patients", "G1359A", "(", "41", "patients", ",", "43.6", "%", ")", "or", "A1359A", "(", "6", "patients", ",", "6.4", "%", ")", "(", "mutant", "type", "group", ")", "had", "the", "genotype", ".", "In", "wild", "and", "mutant", "type", "groups", ",", "weight", ",", "body", "mass", "index", ",", "fat", "mass", ",", "waist", "circumference", "and", "systolic", "blood", "pressure", "decreased", ".", "In", "mutant", "type", "group", ",", "resistin", "(", "4.15", "1.7", "ng/ml", "vs.", "3.90", "2.1", "ng/ml", ":", "P", "<", "0.05", ")", ",", "leptin", "(", "78.4", "69", "ng/ml", "vs", "66.2", "32", "ng/ml", ":", "P", "<", "0.05", ")", "and", "IL-6", "(", "1.40", "1.9", "pg/ml", "vs", "0.81", "1.5", "pg/ml", ":", "P", "<", "0.05", ")", "levels", "decreased", "after", "dietary", "treatment", ".", "CONCLUSION", ":", "The", "novel", "finding", "of", "this", "study", "is", "the", "association", "of", "the", "mutant", "allele", "(", "A1359", ")", "with", "a", "decrease", "of", "resistin", ",", "leptin", "and", "interleukin-6", "secondary", "to", "weight", "loss", "." ]
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16167916
The effects of short-term raloxifene therapy on fibrinolysis markers: TAFI, tPA, and PAI-1. BACKGROUND: Markers of fibrinolysis, thrombin-activatable fibrinolysis inhibitor (TAFI), tissue-type plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) levels were studied for the evaluation of short-term effects of raloxifene administration in postmenopausal women. METHODS: Thirty-nine postmenopausal women with osteopenia or osteoporosis were included in this prospective, controlled clinical study. Twenty-five women were given raloxifene hydrochloride (60 mg/day) plus calcium (500 mg/day). Age-matched controls (n = 14) were given only calcium. Plasma TAFI, tPA, and PAI-1 antigen levels were measured at baseline and after 3 months of treatment by commercially available ELISA kits. Variations of individuals were assessed by Wilcoxon's test. Relationship between those markers and demographic characteristics were investigated. RESULTS: Three months of raloxifene treatment was associated with a significant decrease in the plasma TAFI antigen concentrations (16% change, P < 0.01), and a significant increase in tPA antigen concentrations (25% change, P < 0.05). A significant correlation was found between baseline TAFI antigen concentrations and the duration of amenorrhea (P < 0.05; r = 0.33). CONCLUSION: We suggest that the increased risk of venous thromboembolism due to raloxifene treatment may be related to increased tPA levels, but not TAFI levels.
[ "The", "effects", "of", "short-term", "raloxifene", "therapy", "on", "fibrinolysis", "markers", ":", "TAFI", ",", "tPA", ",", "and", "PAI-1", ".", "BACKGROUND", ":", "Markers", "of", "fibrinolysis", ",", "thrombin-activatable", "fibrinolysis", "inhibitor", "(", "TAFI", ")", ",", "tissue-type", "plasminogen", "activator", "(", "tPA", ")", ",", "and", "plasminogen", "activator", "inhibitor-1", "(", "PAI-1", ")", "levels", "were", "studied", "for", "the", "evaluation", "of", "short-term", "effects", "of", "raloxifene", "administration", "in", "postmenopausal", "women", ".", "METHODS", ":", "Thirty-nine", "postmenopausal", "women", "with", "osteopenia", "or", "osteoporosis", "were", "included", "in", "this", "prospective", ",", "controlled", "clinical", "study", ".", "Twenty-five", "women", "were", "given", "raloxifene", "hydrochloride", "(", "60", "mg/day", ")", "plus", "calcium", "(", "500", "mg/day", ")", ".", "Age-matched", "controls", "(", "n", "=", "14", ")", "were", "given", "only", "calcium", ".", "Plasma", "TAFI", ",", "tPA", ",", "and", "PAI-1", "antigen", "levels", "were", "measured", "at", "baseline", "and", "after", "3", "months", "of", "treatment", "by", "commercially", "available", "ELISA", "kits", ".", "Variations", "of", "individuals", "were", "assessed", "by", "Wilcoxon", "'s", "test", ".", "Relationship", "between", "those", "markers", "and", "demographic", "characteristics", "were", "investigated", ".", "RESULTS", ":", "Three", "months", "of", "raloxifene", "treatment", "was", "associated", "with", "a", "significant", "decrease", "in", "the", "plasma", "TAFI", "antigen", "concentrations", "(", "16", "%", "change", ",", "P", "<", "0.01", ")", ",", "and", "a", "significant", "increase", "in", "tPA", "antigen", "concentrations", "(", "25", "%", "change", ",", "P", "<", "0.05", ")", ".", "A", "significant", "correlation", "was", "found", "between", "baseline", "TAFI", "antigen", "concentrations", "and", "the", "duration", "of", "amenorrhea", "(", "P", "<", "0.05", ";", "r", "=", "0.33", ")", ".", "CONCLUSION", ":", "We", "suggest", "that", "the", "increased", "risk", "of", "venous", "thromboembolism", "due", "to", "raloxifene", "treatment", "may", "be", "related", "to", "increased", "tPA", "levels", ",", "but", "not", "TAFI", "levels", "." ]
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16781314
Ectodermal dysplasia-skin fragility syndrome resulting from a new homozygous mutation, 888delC, in the desmosomal protein plakophilin 1. We report an unusual case of an inherited disorder of the desmosomal protein plakophilin 1, resulting in ectodermal dysplasia-skin fragility syndrome. The affected 6-year-old boy had red skin at birth and subsequently developed skin fragility, progressive plantar keratoderma, nail dystrophy, and alopecia. Skin biopsy revealed widening of intercellular spaces in the epidermis and a reduced number of small, poorly formed desmosomes. Mutation analysis of the plakophilin 1 gene PKP1 revealed a homozygous deletion of C at nucleotide 888 within exon 5. This mutation differs from the PKP1 gene pathology reported in 8 previously published individuals with this rare genodermatosis. However, all cases show similar clinical features, highlighting the importance of functional plakophilin 1 in maintaining desmosomal adhesion in skin, as well as the role of this protein in aspects of ectodermal development.
[ "Ectodermal", "dysplasia-skin", "fragility", "syndrome", "resulting", "from", "a", "new", "homozygous", "mutation", ",", "888delC", ",", "in", "the", "desmosomal", "protein", "plakophilin", "1", ".", "We", "report", "an", "unusual", "case", "of", "an", "inherited", "disorder", "of", "the", "desmosomal", "protein", "plakophilin", "1", ",", "resulting", "in", "ectodermal", "dysplasia-skin", "fragility", "syndrome", ".", "The", "affected", "6-year-old", "boy", "had", "red", "skin", "at", "birth", "and", "subsequently", "developed", "skin", "fragility", ",", "progressive", "plantar", "keratoderma", ",", "nail", "dystrophy", ",", "and", "alopecia", ".", "Skin", "biopsy", "revealed", "widening", "of", "intercellular", "spaces", "in", "the", "epidermis", "and", "a", "reduced", "number", "of", "small", ",", "poorly", "formed", "desmosomes", ".", "Mutation", "analysis", "of", "the", "plakophilin", "1", "gene", "PKP1", "revealed", "a", "homozygous", "deletion", "of", "C", "at", "nucleotide", "888", "within", "exon", "5", ".", "This", "mutation", "differs", "from", "the", "PKP1", "gene", "pathology", "reported", "in", "8", "previously", "published", "individuals", "with", "this", "rare", "genodermatosis", ".", "However", ",", "all", "cases", "show", "similar", "clinical", "features", ",", "highlighting", "the", "importance", "of", "functional", "plakophilin", "1", "in", "maintaining", "desmosomal", "adhesion", "in", "skin", ",", "as", "well", "as", "the", "role", "of", "this", "protein", "in", "aspects", "of", "ectodermal", "development", "." ]
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16843501
DNA damage and repair in gastric cancer--a correlation with the hOGG1 and RAD51 genes polymorphisms. The cell's susceptibility to mutagens and its ability to repair DNA lesions are important for cancer induction, promotion and progression. Both the mutagens' sensitivity and the efficacy of DNA repair may be affected by variation in several genes, including DNA repair genes. The hOGG1 gene encodes glycosylase of base excision repair and RAD51 specifies a key protein in homologues recombination repair. Both can be involved in the repair of oxidative DNA lesions, which can contribute to stomach cancer. In the present work we determined the level of basal and oxidative DNA damage and the kinetics of removal of DNA damage induced by hydrogen peroxide in peripheral blood lymphocytes of 30 gastric cancer patients and 30 healthy individuals. The metrics from DNA damage and repair study were correlated with the genotypes of common polymorphisms of the hOGG1 and RAD51 genes: a G-->C transversion at 1245 position of the hOGG1 gene producing a Ser-->Cys substitution at the codon 326 (the Ser326Cys polymorphism) and a G-->C substitution at position 135 (5'-untranslated region) of the RAD51 gene (the G135C polymorphism). DNA damage and repair were evaluated by alkaline single cell gel electrophoresis (comet assay) assisted by DNA repair enzymes: endonuclease III (Nth) and formamidopyrimidine-DNA glycosylase (Fpg), preferentially recognizing oxidized DNA bases. The genotypes of the polymorphism were determined by restriction fragment length polymorphism PCR. We observed a strong association between gastric cancer occurrence, impaired DNA repair in human lymphocytes and the G/C genotype of the G135C polymorphism of the RAD51 gene. Moreover, there was a strong correlation between that genotype and stomach cancer occurrence in subjects with high level of oxidatively damaged DNA. We did not observe any correlation between the Ser1245Cys polymorphism of the hOGG1 gene and gastric cancer, including subjects with impaired DNA repair and/or high levels of endogenous oxidative DNA lesions. Therefore, our result suggest that the G135C polymorphism of the RAD51 gene may be linked with gastric cancer by the modulation of the cellular response to oxidative stress and this polymorphism may be a useful additional marker in this disease along with the genetic or/and environmental indicators of oxidative stress.
[ "DNA", "damage", "and", "repair", "in", "gastric", "cancer", "--", "a", "correlation", "with", "the", "hOGG1", "and", "RAD51", "genes", "polymorphisms", ".", "The", "cell", "'s", "susceptibility", "to", "mutagens", "and", "its", "ability", "to", "repair", "DNA", "lesions", "are", "important", "for", "cancer", "induction", ",", "promotion", "and", "progression", ".", "Both", "the", "mutagens", "'", "sensitivity", "and", "the", "efficacy", "of", "DNA", "repair", "may", "be", "affected", "by", "variation", "in", "several", "genes", ",", "including", "DNA", "repair", "genes", ".", "The", "hOGG1", "gene", "encodes", "glycosylase", "of", "base", "excision", "repair", "and", "RAD51", "specifies", "a", "key", "protein", "in", "homologues", "recombination", "repair", ".", "Both", "can", "be", "involved", "in", "the", "repair", "of", "oxidative", "DNA", "lesions", ",", "which", "can", "contribute", "to", "stomach", "cancer", ".", "In", "the", "present", "work", "we", "determined", "the", "level", "of", "basal", "and", "oxidative", "DNA", "damage", "and", "the", "kinetics", "of", "removal", "of", "DNA", "damage", "induced", "by", "hydrogen", "peroxide", "in", "peripheral", "blood", "lymphocytes", "of", "30", "gastric", "cancer", "patients", "and", "30", "healthy", "individuals", ".", "The", "metrics", "from", "DNA", "damage", "and", "repair", "study", "were", "correlated", "with", "the", "genotypes", "of", "common", "polymorphisms", "of", "the", "hOGG1", "and", "RAD51", "genes", ":", "a", "G", "--", ">", "C", "transversion", "at", "1245", "position", "of", "the", "hOGG1", "gene", "producing", "a", "Ser", "--", ">", "Cys", "substitution", "at", "the", "codon", "326", "(", "the", "Ser326Cys", "polymorphism", ")", "and", "a", "G", "--", ">", "C", "substitution", "at", "position", "135", "(", "5'-untranslated", "region", ")", "of", "the", "RAD51", "gene", "(", "the", "G135C", "polymorphism", ")", ".", "DNA", "damage", "and", "repair", "were", "evaluated", "by", "alkaline", "single", "cell", "gel", "electrophoresis", "(", "comet", "assay", ")", "assisted", "by", "DNA", "repair", "enzymes", ":", "endonuclease", "III", "(", "Nth", ")", "and", "formamidopyrimidine-DNA", "glycosylase", "(", "Fpg", ")", ",", "preferentially", "recognizing", "oxidized", "DNA", "bases", ".", "The", "genotypes", "of", "the", "polymorphism", "were", "determined", "by", "restriction", "fragment", "length", "polymorphism", "PCR", ".", "We", "observed", "a", "strong", "association", "between", "gastric", "cancer", "occurrence", ",", "impaired", "DNA", "repair", "in", "human", "lymphocytes", "and", "the", "G/C", "genotype", "of", "the", "G135C", "polymorphism", "of", "the", "RAD51", "gene", ".", "Moreover", ",", "there", "was", "a", "strong", "correlation", "between", "that", "genotype", "and", "stomach", "cancer", "occurrence", "in", "subjects", "with", "high", "level", "of", "oxidatively", "damaged", "DNA", ".", "We", "did", "not", "observe", "any", "correlation", "between", "the", "Ser1245Cys", "polymorphism", "of", "the", "hOGG1", "gene", "and", "gastric", "cancer", ",", "including", "subjects", "with", "impaired", "DNA", "repair", "and/or", "high", "levels", "of", "endogenous", "oxidative", "DNA", "lesions", ".", "Therefore", ",", "our", "result", "suggest", "that", "the", "G135C", "polymorphism", "of", "the", "RAD51", "gene", "may", "be", "linked", "with", "gastric", "cancer", "by", "the", "modulation", "of", "the", "cellular", "response", "to", "oxidative", "stress", "and", "this", "polymorphism", "may", "be", "a", "useful", "additional", "marker", "in", "this", "disease", "along", "with", "the", "genetic", "or/and", "environmental", "indicators", "of", "oxidative", "stress", "." ]
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17221831
The G51S purine nucleoside phosphorylase polymorphism is associated with cognitive decline in Alzheimer's disease patients. Alzheimer's disease (AD) is a polygenic and multifactorial complex disease, whose etiopathology is still unclear, however several genetic factors have shown to increase the risk of developing the disease. Purine nucleotides and nucleosides play an important role in the brain. Besides their role in neurotransmission and neuromodulation, they are involved in trophic factor release, apoptosis, and inflammatory responses. These mediators may also have a pivotal role in the control of neurodegenerative processes associated with AD. In this report the distribution of the exonic G/A single nucleotide polymorphism (SNP) in purine nucleoside phosphorylase (PNP) gene, resulting in the amino acid substitution serine to glycine at position 51 (G51S), was investigated in a large population of AD patients (n=321) and non-demented control (n=208). The PNP polymorphism distribution was not different between patients and controls. The polymorphism distribution was also analyzed in AD patients stratified according to differential progressive rate of cognitive decline during a 2-year follow-up. An increased representation of the PNP AA genotype was observed in AD patients with fast cognitive deterioration in comparison with that from patients with slow deterioration rate. Our findings suggest that the G51S PNP polymorphism is associated with a faster rate of cognitive decline in AD patients, highlighting the important role of purine metabolism in the progression of this neurodegenerative disorder.
[ "The", "G51S", "purine", "nucleoside", "phosphorylase", "polymorphism", "is", "associated", "with", "cognitive", "decline", "in", "Alzheimer", "'s", "disease", "patients", ".", "Alzheimer", "'s", "disease", "(", "AD", ")", "is", "a", "polygenic", "and", "multifactorial", "complex", "disease", ",", "whose", "etiopathology", "is", "still", "unclear", ",", "however", "several", "genetic", "factors", "have", "shown", "to", "increase", "the", "risk", "of", "developing", "the", "disease", ".", "Purine", "nucleotides", "and", "nucleosides", "play", "an", "important", "role", "in", "the", "brain", ".", "Besides", "their", "role", "in", "neurotransmission", "and", "neuromodulation", ",", "they", "are", "involved", "in", "trophic", "factor", "release", ",", "apoptosis", ",", "and", "inflammatory", "responses", ".", "These", "mediators", "may", "also", "have", "a", "pivotal", "role", "in", "the", "control", "of", "neurodegenerative", "processes", "associated", "with", "AD", ".", "In", "this", "report", "the", "distribution", "of", "the", "exonic", "G/A", "single", "nucleotide", "polymorphism", "(", "SNP", ")", "in", "purine", "nucleoside", "phosphorylase", "(", "PNP", ")", "gene", ",", "resulting", "in", "the", "amino", "acid", "substitution", "serine", "to", "glycine", "at", "position", "51", "(", "G51S", ")", ",", "was", "investigated", "in", "a", "large", "population", "of", "AD", "patients", "(", "n=321", ")", "and", "non-demented", "control", "(", "n=208", ")", ".", "The", "PNP", "polymorphism", "distribution", "was", "not", "different", "between", "patients", "and", "controls", ".", "The", "polymorphism", "distribution", "was", "also", "analyzed", "in", "AD", "patients", "stratified", "according", "to", "differential", "progressive", "rate", "of", "cognitive", "decline", "during", "a", "2-year", "follow-up", ".", "An", "increased", "representation", "of", "the", "PNP", "AA", "genotype", "was", "observed", "in", "AD", "patients", "with", "fast", "cognitive", "deterioration", "in", "comparison", "with", "that", "from", "patients", "with", "slow", "deterioration", "rate", ".", "Our", "findings", "suggest", "that", "the", "G51S", "PNP", "polymorphism", "is", "associated", "with", "a", "faster", "rate", "of", "cognitive", "decline", "in", "AD", "patients", ",", "highlighting", "the", "important", "role", "of", "purine", "metabolism", "in", "the", "progression", "of", "this", "neurodegenerative", "disorder", "." ]
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17286451
Retinoblastoma in India : microsatellite analysis and its application in genetic counseling. OBJECTIVES: This study was conducted with two objectives. The first was to estimate the frequency of loss of heterozygosity (LOH) of the RB1 gene as a mechanism in disease causation in tumors of patients from India. The second objective was to employ RB1 molecular deletion and microsatellite-based linkage analysis as laboratory tools, while counseling families with a history of retinoblastoma (RB). METHODS: DNA was extracted from peripheral blood and tumors of 54 RB patients and their relatives. Eight fluorescent microsatellite markers, both intragenic and flanking the RB1 gene, were used. After PCR amplification, samples were run on an ABI PRISM 310 genetic analyzer for LOH, deletion detection, and haplotype generation. RESULTS: LOH was found in conjunction with tumor formation in 72.9% of RB patients (39/54 patients; p=0.001; 95% CI 0.6028, 0.8417); however, we could not associate various other clinical parameters of RB patients with the presence or absence of RB1 LOH. Seven germline deletions (13% of RB patients) were identified, and the maternal allele was more frequently lost (p=0.01). A disease co-segregating haplotype was detected in two hereditary autosomal dominant cases. CONCLUSION: LOH of the RB1 gene could play an important role in tumor formation. Large deletions involving RB1 were observed, and a disease co-segregating haplotype was used for indirect genetic testing. This is the first report from India where molecular testing has been applied for RB families in conjunction with genetic counseling. In tertiary ophthalmic practice in India, there is an emerging trend towards the application of genetical knowledge in clinical practice.
[ "Retinoblastoma", "in", "India", ":", "microsatellite", "analysis", "and", "its", "application", "in", "genetic", "counseling", ".", "OBJECTIVES", ":", "This", "study", "was", "conducted", "with", "two", "objectives", ".", "The", "first", "was", "to", "estimate", "the", "frequency", "of", "loss", "of", "heterozygosity", "(", "LOH", ")", "of", "the", "RB1", "gene", "as", "a", "mechanism", "in", "disease", "causation", "in", "tumors", "of", "patients", "from", "India", ".", "The", "second", "objective", "was", "to", "employ", "RB1", "molecular", "deletion", "and", "microsatellite-based", "linkage", "analysis", "as", "laboratory", "tools", ",", "while", "counseling", "families", "with", "a", "history", "of", "retinoblastoma", "(", "RB", ")", ".", "METHODS", ":", "DNA", "was", "extracted", "from", "peripheral", "blood", "and", "tumors", "of", "54", "RB", "patients", "and", "their", "relatives", ".", "Eight", "fluorescent", "microsatellite", "markers", ",", "both", "intragenic", "and", "flanking", "the", "RB1", "gene", ",", "were", "used", ".", "After", "PCR", "amplification", ",", "samples", "were", "run", "on", "an", "ABI", "PRISM", "310", "genetic", "analyzer", "for", "LOH", ",", "deletion", "detection", ",", "and", "haplotype", "generation", ".", "RESULTS", ":", "LOH", "was", "found", "in", "conjunction", "with", "tumor", "formation", "in", "72.9", "%", "of", "RB", "patients", "(", "39/54", "patients", ";", "p=0.001", ";", "95", "%", "CI", "0.6028", ",", "0.8417", ")", ";", "however", ",", "we", "could", "not", "associate", "various", "other", "clinical", "parameters", "of", "RB", "patients", "with", "the", "presence", "or", "absence", "of", "RB1", "LOH", ".", "Seven", "germline", "deletions", "(", "13", "%", "of", "RB", "patients", ")", "were", "identified", ",", "and", "the", "maternal", "allele", "was", "more", "frequently", "lost", "(", "p=0.01", ")", ".", "A", "disease", "co-segregating", "haplotype", "was", "detected", "in", "two", "hereditary", "autosomal", "dominant", "cases", ".", "CONCLUSION", ":", "LOH", "of", "the", "RB1", "gene", "could", "play", "an", "important", "role", "in", "tumor", "formation", ".", "Large", "deletions", "involving", "RB1", "were", "observed", ",", "and", "a", "disease", "co-segregating", "haplotype", "was", "used", "for", "indirect", "genetic", "testing", ".", "This", "is", "the", "first", "report", "from", "India", "where", "molecular", "testing", "has", "been", "applied", "for", "RB", "families", "in", "conjunction", "with", "genetic", "counseling", ".", "In", "tertiary", "ophthalmic", "practice", "in", "India", ",", "there", "is", "an", "emerging", "trend", "towards", "the", "application", "of", "genetical", "knowledge", "in", "clinical", "practice", "." ]
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17327131
Molecular analysis of the CYP2F1 gene: identification of a frequent non-functional allelic variant. The CYP2F1 is a human cytochrome P450 that is selectively expressed in lung tissue and involved in the metabolism of various pneumotoxicants with potential carcinogenic effects. In the present study, we report the first systematic investigation of the genetic polymorphism of this enzyme. We analyzed the nucleotidic sequence of the CYP2F1 gene in DNA samples from 90 French Caucasians consisting in 44 patients with lung cancer and 46 control individuals, using single-strand conformation polymorphism analysis of PCR products (PCR-SSCP). We identified 24 novel mutations distributed in the promoter region of the gene, as well as in the coding regions and their flanking intronic sequences. In addition to the wild-type CYP2F1*1 allele, seven allelic variant, CYP2F1*2A, *2B, *3, *4, *5A, *5B and *6, were characterized. The most frequent allelic variant, CYP2F1*2A (25.6%), harbors a combination of 9 mutations, including 2 missense mutations (Asp218Asn and Gln266His) and a 1-bp insertion (c.14_15insC) that creates a premature stop codon in exon 2, probably leading to the synthesis of a severely truncated protein with no catalytic activity. The identification of around 7% of homozygotes for the frameshift mutation in our Caucasian population suggests the existence of an interindividual variation of the CYP2F1 activity and, consequently, the possibility of interindividual differences in the toxic response to some pneumotoxicants and in the susceptibility to certain chemically induced diseases. However, our preliminary results did not show any evidence that the CYP2F1 genetic polymorphism has implications in the pathogenesis of lung cancer.
[ "Molecular", "analysis", "of", "the", "CYP2F1", "gene", ":", "identification", "of", "a", "frequent", "non-functional", "allelic", "variant", ".", "The", "CYP2F1", "is", "a", "human", "cytochrome", "P450", "that", "is", "selectively", "expressed", "in", "lung", "tissue", "and", "involved", "in", "the", "metabolism", "of", "various", "pneumotoxicants", "with", "potential", "carcinogenic", "effects", ".", "In", "the", "present", "study", ",", "we", "report", "the", "first", "systematic", "investigation", "of", "the", "genetic", "polymorphism", "of", "this", "enzyme", ".", "We", "analyzed", "the", "nucleotidic", "sequence", "of", "the", "CYP2F1", "gene", "in", "DNA", "samples", "from", "90", "French", "Caucasians", "consisting", "in", "44", "patients", "with", "lung", "cancer", "and", "46", "control", "individuals", ",", "using", "single-strand", "conformation", "polymorphism", "analysis", "of", "PCR", "products", "(", "PCR-SSCP", ")", ".", "We", "identified", "24", "novel", "mutations", "distributed", "in", "the", "promoter", "region", "of", "the", "gene", ",", "as", "well", "as", "in", "the", "coding", "regions", "and", "their", "flanking", "intronic", "sequences", ".", "In", "addition", "to", "the", "wild-type", "CYP2F1", "*", "1", "allele", ",", "seven", "allelic", "variant", ",", "CYP2F1", "*", "2A", ",", "*", "2B", ",", "*", "3", ",", "*", "4", ",", "*", "5A", ",", "*", "5B", "and", "*", "6", ",", "were", "characterized", ".", "The", "most", "frequent", "allelic", "variant", ",", "CYP2F1", "*", "2A", "(", "25.6", "%", ")", ",", "harbors", "a", "combination", "of", "9", "mutations", ",", "including", "2", "missense", "mutations", "(", "Asp218Asn", "and", "Gln266His", ")", "and", "a", "1-bp", "insertion", "(", "c.14_15insC", ")", "that", "creates", "a", "premature", "stop", "codon", "in", "exon", "2", ",", "probably", "leading", "to", "the", "synthesis", "of", "a", "severely", "truncated", "protein", "with", "no", "catalytic", "activity", ".", "The", "identification", "of", "around", "7", "%", "of", "homozygotes", "for", "the", "frameshift", "mutation", "in", "our", "Caucasian", "population", "suggests", "the", "existence", "of", "an", "interindividual", "variation", "of", "the", "CYP2F1", "activity", "and", ",", "consequently", ",", "the", "possibility", "of", "interindividual", "differences", "in", "the", "toxic", "response", "to", "some", "pneumotoxicants", "and", "in", "the", "susceptibility", "to", "certain", "chemically", "induced", "diseases", ".", "However", ",", "our", "preliminary", "results", "did", "not", "show", "any", "evidence", "that", "the", "CYP2F1", "genetic", "polymorphism", "has", "implications", "in", "the", "pathogenesis", "of", "lung", "cancer", "." ]
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19365571
Macular corneal dystrophy in a Chinese family related with novel mutations of CHST6. PURPOSE: To identify mutations in the carbohydrate sulfotransferase gene (CHST6) for a Chinese family with macular corneal dystrophy (MCD) and to investigate the histopathological changes in the affected cornea. METHODS: A corneal button of the proband was obtained by penetrating keratoplasty. The half button and ultrathin sections from the other half button were examined with special stains under a light microscope (LM) and an electron microscope (EM) separately. Genomic DNA was extracted from peripheral blood of 11 family members, and the coding region of CHST6 was amplified by the polymerase chain reaction (PCR) method. The PCR products were analyzed by direct sequencing and restriction enzyme digestion. RESULTS: The positive reaction to colloidal iron stain (extracellular blue accumulations in the stroma) was detected under light microscopy. Transmission electron microscopy revealed the enlargement of smooth endoplasmic reticulum and the presence of intracytoplasmic vacuoles. The compound heterozygous mutations, c.892C>T and c.1072T>C, were identified in exon 3 of CHST6 in three patients. The two transversions resulted in the substitution of a stop codon for glutamine at codon 298 (p.Q298X) and a missense mutation at codon 358, tyrosine to histidine (p.Y358H). The six unaffected family individuals carried alternative heterozygous mutations. These two mutations were not detected in any of the 100 control subjects. CONCLUSIONS: Those novel compound heterozygous mutations were thought to contribute to the loss of CHST6 function, which induced the abnormal metabolism of keratan sulfate (KS) that deposited in the corneal stroma. It could be proved by the observation of a positive stain reaction and the enlarged collagen fibers as well as hyperplastic fibroblasts under microscopes.
[ "Macular", "corneal", "dystrophy", "in", "a", "Chinese", "family", "related", "with", "novel", "mutations", "of", "CHST6", ".", "PURPOSE", ":", "To", "identify", "mutations", "in", "the", "carbohydrate", "sulfotransferase", "gene", "(", "CHST6", ")", "for", "a", "Chinese", "family", "with", "macular", "corneal", "dystrophy", "(", "MCD", ")", "and", "to", "investigate", "the", "histopathological", "changes", "in", "the", "affected", "cornea", ".", "METHODS", ":", "A", "corneal", "button", "of", "the", "proband", "was", "obtained", "by", "penetrating", "keratoplasty", ".", "The", "half", "button", "and", "ultrathin", "sections", "from", "the", "other", "half", "button", "were", "examined", "with", "special", "stains", "under", "a", "light", "microscope", "(", "LM", ")", "and", "an", "electron", "microscope", "(", "EM", ")", "separately", ".", "Genomic", "DNA", "was", "extracted", "from", "peripheral", "blood", "of", "11", "family", "members", ",", "and", "the", "coding", "region", "of", "CHST6", "was", "amplified", "by", "the", "polymerase", "chain", "reaction", "(", "PCR", ")", "method", ".", "The", "PCR", "products", "were", "analyzed", "by", "direct", "sequencing", "and", "restriction", "enzyme", "digestion", ".", "RESULTS", ":", "The", "positive", "reaction", "to", "colloidal", "iron", "stain", "(", "extracellular", "blue", "accumulations", "in", "the", "stroma", ")", "was", "detected", "under", "light", "microscopy", ".", "Transmission", "electron", "microscopy", "revealed", "the", "enlargement", "of", "smooth", "endoplasmic", "reticulum", "and", "the", "presence", "of", "intracytoplasmic", "vacuoles", ".", "The", "compound", "heterozygous", "mutations", ",", "c.892C", ">", "T", "and", "c.1072T", ">", "C", ",", "were", "identified", "in", "exon", "3", "of", "CHST6", "in", "three", "patients", ".", "The", "two", "transversions", "resulted", "in", "the", "substitution", "of", "a", "stop", "codon", "for", "glutamine", "at", "codon", "298", "(", "p.Q298X", ")", "and", "a", "missense", "mutation", "at", "codon", "358", ",", "tyrosine", "to", "histidine", "(", "p.Y358H", ")", ".", "The", "six", "unaffected", "family", "individuals", "carried", "alternative", "heterozygous", "mutations", ".", "These", "two", "mutations", "were", "not", "detected", "in", "any", "of", "the", "100", "control", "subjects", ".", "CONCLUSIONS", ":", "Those", "novel", "compound", "heterozygous", "mutations", "were", "thought", "to", "contribute", "to", "the", "loss", "of", "CHST6", "function", ",", "which", "induced", "the", "abnormal", "metabolism", "of", "keratan", "sulfate", "(", "KS", ")", "that", "deposited", "in", "the", "corneal", "stroma", ".", "It", "could", "be", "proved", "by", "the", "observation", "of", "a", "positive", "stain", "reaction", "and", "the", "enlarged", "collagen", "fibers", "as", "well", "as", "hyperplastic", "fibroblasts", "under", "microscopes", "." ]
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19642243
Acute renal failure in patients with AIDS on tenofovir while receiving prolonged vancomycin course for osteomyelitis. Renal failure developed after a prolonged course of vancomycin therapy in 2 patients who were receiving tenofovir disoproxil fumarate as part of an antiretroviral regimen. Tenofovir has been implicated in the development of Fanconi syndrome and renal insufficiency because of its effects on the proximal renal tubule. Vancomycin nephrotoxicity is infrequent but may result from coadministration with a nephrotoxic agent. Clinicians should be aware that tenofovir may raise the risk of renal failure during prolonged administration of vancomycin.
[ "Acute", "renal", "failure", "in", "patients", "with", "AIDS", "on", "tenofovir", "while", "receiving", "prolonged", "vancomycin", "course", "for", "osteomyelitis", ".", "Renal", "failure", "developed", "after", "a", "prolonged", "course", "of", "vancomycin", "therapy", "in", "2", "patients", "who", "were", "receiving", "tenofovir", "disoproxil", "fumarate", "as", "part", "of", "an", "antiretroviral", "regimen", ".", "Tenofovir", "has", "been", "implicated", "in", "the", "development", "of", "Fanconi", "syndrome", "and", "renal", "insufficiency", "because", "of", "its", "effects", "on", "the", "proximal", "renal", "tubule", ".", "Vancomycin", "nephrotoxicity", "is", "infrequent", "but", "may", "result", "from", "coadministration", "with", "a", "nephrotoxic", "agent", ".", "Clinicians", "should", "be", "aware", "that", "tenofovir", "may", "raise", "the", "risk", "of", "renal", "failure", "during", "prolonged", "administration", "of", "vancomycin", "." ]
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16410744
Genetic alterations in primary glioblastomas in Japan. Current knowledge of genetic alterations in glioblastomas is based largely on genetic analyses of tumors from mainly caucasian patients in the United States and Europe. In the present study, screening for several key genetic alterations was performed on 77 primary (de novo) glioblastomas in Japanese patients. SSCP followed by DNA sequencing revealed TP53 mutations in 16 of 73 (22%) glioblastomas and PTEN mutations in 13 of 63 (21%) cases analyzed. Polymerase chain reaction (PCR) showed EGFR amplification in 25 of 77 (32%) cases and p16 homozygous deletion in 32 of 77 (42%) cases. Quantitative microsatellite analysis revealed LOH 10q in 41 of 59 (69%) glioblastomas. The frequencies of these genetic alterations were similar to those reported for primary glioblastomas at the population level in Switzerland. As previously observed for glioblastomas in Europe, there was a positive association between EGFR amplification and p16 deletion (p=0.009), whereas there was an inverse association between TP53 mutations and p16 deletion (p=0.049) in glioblastomas in Japan. Multivariate analyses showed that radiotherapy was significantly predictive for longer survival of glioblastoma patients (p=0.002). SSCP followed by DNA sequencing of the kinase domain (exons 18-21) of the EGFR gene revealed mutations in 2 ou of 69 (3%) glioblastomas in Japan and in 4 of 81 (5%) glioblastomas in Switzerland. The allele frequencies of polymorphisms at codon 787 CAG/CAA (Gln/Gln) in glioblastomas in Japan were G/G (82.4%), G/A (10.8%), A/A (6.8%), corresponding to G 0.878 versus A 0.122, significantly different from those in glioblastomas in Switzerland: G/G (27.2%), G/A (28.4%), A/A (44.4%), corresponding to G 0.414 versus A 0.586 (p < 0.0001). These results suggest that primary glioblastomas in Japan show genetic alterations similar to those in Switzerland, suggesting a similar molecular basis in caucasians and Asians, despite different genetic backgrounds, including different status of a polymorphism in the EGFR gene.
[ "Genetic", "alterations", "in", "primary", "glioblastomas", "in", "Japan", ".", "Current", "knowledge", "of", "genetic", "alterations", "in", "glioblastomas", "is", "based", "largely", "on", "genetic", "analyses", "of", "tumors", "from", "mainly", "caucasian", "patients", "in", "the", "United", "States", "and", "Europe", ".", "In", "the", "present", "study", ",", "screening", "for", "several", "key", "genetic", "alterations", "was", "performed", "on", "77", "primary", "(", "de", "novo", ")", "glioblastomas", "in", "Japanese", "patients", ".", "SSCP", "followed", "by", "DNA", "sequencing", "revealed", "TP53", "mutations", "in", "16", "of", "73", "(", "22", "%", ")", "glioblastomas", "and", "PTEN", "mutations", "in", "13", "of", "63", "(", "21", "%", ")", "cases", "analyzed", ".", "Polymerase", "chain", "reaction", "(", "PCR", ")", "showed", "EGFR", "amplification", "in", "25", "of", "77", "(", "32", "%", ")", "cases", "and", "p16", "homozygous", "deletion", "in", "32", "of", "77", "(", "42", "%", ")", "cases", ".", "Quantitative", "microsatellite", "analysis", "revealed", "LOH", "10q", "in", "41", "of", "59", "(", "69", "%", ")", "glioblastomas", ".", "The", "frequencies", "of", "these", "genetic", "alterations", "were", "similar", "to", "those", "reported", "for", "primary", "glioblastomas", "at", "the", "population", "level", "in", "Switzerland", ".", "As", "previously", "observed", "for", "glioblastomas", "in", "Europe", ",", "there", "was", "a", "positive", "association", "between", "EGFR", "amplification", "and", "p16", "deletion", "(", "p=0.009", ")", ",", "whereas", "there", "was", "an", "inverse", "association", "between", "TP53", "mutations", "and", "p16", "deletion", "(", "p=0.049", ")", "in", "glioblastomas", "in", "Japan", ".", "Multivariate", "analyses", "showed", "that", "radiotherapy", "was", "significantly", "predictive", "for", "longer", "survival", "of", "glioblastoma", "patients", "(", "p=0.002", ")", ".", "SSCP", "followed", "by", "DNA", "sequencing", "of", "the", "kinase", "domain", "(", "exons", "18-21", ")", "of", "the", "EGFR", "gene", "revealed", "mutations", "in", "2", "ou", "of", "69", "(", "3", "%", ")", "glioblastomas", "in", "Japan", "and", "in", "4", "of", "81", "(", "5", "%", ")", "glioblastomas", "in", "Switzerland", ".", "The", "allele", "frequencies", "of", "polymorphisms", "at", "codon", "787", "CAG/CAA", "(", "Gln/Gln", ")", "in", "glioblastomas", "in", "Japan", "were", "G/G", "(", "82.4", "%", ")", ",", "G/A", "(", "10.8", "%", ")", ",", "A/A", "(", "6.8", "%", ")", ",", "corresponding", "to", "G", "0.878", "versus", "A", "0.122", ",", "significantly", "different", "from", "those", "in", "glioblastomas", "in", "Switzerland", ":", "G/G", "(", "27.2", "%", ")", ",", "G/A", "(", "28.4", "%", ")", ",", "A/A", "(", "44.4", "%", ")", ",", "corresponding", "to", "G", "0.414", "versus", "A", "0.586", "(", "p", "<", "0.0001", ")", ".", "These", "results", "suggest", "that", "primary", "glioblastomas", "in", "Japan", "show", "genetic", "alterations", "similar", "to", "those", "in", "Switzerland", ",", "suggesting", "a", "similar", "molecular", "basis", "in", "caucasians", "and", "Asians", ",", "despite", "different", "genetic", "backgrounds", ",", "including", "different", "status", "of", "a", "polymorphism", "in", "the", "EGFR", "gene", "." ]
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16526029
Evaluation of RGS4 as a candidate gene for schizophrenia. Several studies have suggested that the regulator of G-protein signaling 4 (RGS4) may be a positional and functional candidate gene for schizophrenia. Three single nucleotide polymorphisms (SNP) located at the promoter region (SNP4 and SNP7) and the intron 1 (SNP18) of RGS4 have been verified in different ethnic groups. Positive results have been reported in these SNPs with different numbers of SNP combinatory haplotypes. In this study, these three SNP markers were genotyped in 218 schizophrenia pedigrees of Taiwan (864 individuals) for association analysis. Among these three SNPs, neither SNP4, SNP7, SNP18 has shown significant association with schizophrenia in single locus association analysis, nor any compositions of the three SNP haplotypes has shown significantly associations with the DSM-IV diagnosed schizophrenia. Our results fail to support the RGS4 as a candidate gene for schizophrenia when evaluated from these three SNP markers.
[ "Evaluation", "of", "RGS4", "as", "a", "candidate", "gene", "for", "schizophrenia", ".", "Several", "studies", "have", "suggested", "that", "the", "regulator", "of", "G-protein", "signaling", "4", "(", "RGS4", ")", "may", "be", "a", "positional", "and", "functional", "candidate", "gene", "for", "schizophrenia", ".", "Three", "single", "nucleotide", "polymorphisms", "(", "SNP", ")", "located", "at", "the", "promoter", "region", "(", "SNP4", "and", "SNP7", ")", "and", "the", "intron", "1", "(", "SNP18", ")", "of", "RGS4", "have", "been", "verified", "in", "different", "ethnic", "groups", ".", "Positive", "results", "have", "been", "reported", "in", "these", "SNPs", "with", "different", "numbers", "of", "SNP", "combinatory", "haplotypes", ".", "In", "this", "study", ",", "these", "three", "SNP", "markers", "were", "genotyped", "in", "218", "schizophrenia", "pedigrees", "of", "Taiwan", "(", "864", "individuals", ")", "for", "association", "analysis", ".", "Among", "these", "three", "SNPs", ",", "neither", "SNP4", ",", "SNP7", ",", "SNP18", "has", "shown", "significant", "association", "with", "schizophrenia", "in", "single", "locus", "association", "analysis", ",", "nor", "any", "compositions", "of", "the", "three", "SNP", "haplotypes", "has", "shown", "significantly", "associations", "with", "the", "DSM-IV", "diagnosed", "schizophrenia", ".", "Our", "results", "fail", "to", "support", "the", "RGS4", "as", "a", "candidate", "gene", "for", "schizophrenia", "when", "evaluated", "from", "these", "three", "SNP", "markers", "." ]
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17065198
Analysis of skin cancer risk factors in immunosuppressed renal transplant patients shows high levels of UV-specific tandem CC to TT mutations of the p53 gene. Immunosuppressed renal transplant recipients (RTRs) are predisposed to non-melanoma skin cancers (NMSCs), predominantly squamous cell carcinomas (SCCs). We have analyzed skin lesions from RTRs with aggressive tumors for p53 gene modifications, the presence of Human Papillomas Virus (HPV) DNA in relation to the p53 codon 72 genotype and polymorphisms of the XPD repair gene. We detected 24 p53 mutations in 15/25 (60%) NMSCs, 1 deletion and 23 base substitutions, the majority (78%) being UV-specific C to T transitions at bipyrimidine sites. Importantly, 35% (6/17) are tandem mutations, including 4 UV signature CC to TT transitions possibly linked to modulated DNA repair caused by the immunosuppressive drug cyclosporin A (CsA). We found 8 p53 mutations in 7/17 (41%) precancerous actinic keratosis (AK), suggesting that p53 mutations are early events in RTR skin carcinogenesis. Immunohistochemical analysis shows a good correlation between p53 accumulation and mutations. HPV DNA was detected in 78% of skin lesions (60% Basal Cell Carcinomas, 82%AK and 79% SCCs). Thus, immunosuppression has increased the risk of infections by HPVs, predominantly epidermodysplasia verruciformis, speculated to play a role in skin cancer development. No association is found between HPV status and p53 mutation. Moreover, p53 codon 72 or frequencies of three XPD genotypes of RTRs are comparable with control populations. The p53 mutation spectrum, presenting a high level of CC to TT mutations, shows that the UV component of sunlight is the major risk factor and modulated DNA repair by immunosuppressive drug treatment may be significant in the skin carcinogenesis of RTRs.
[ "Analysis", "of", "skin", "cancer", "risk", "factors", "in", "immunosuppressed", "renal", "transplant", "patients", "shows", "high", "levels", "of", "UV-specific", "tandem", "CC", "to", "TT", "mutations", "of", "the", "p53", "gene", ".", "Immunosuppressed", "renal", "transplant", "recipients", "(", "RTRs", ")", "are", "predisposed", "to", "non-melanoma", "skin", "cancers", "(", "NMSCs", ")", ",", "predominantly", "squamous", "cell", "carcinomas", "(", "SCCs", ")", ".", "We", "have", "analyzed", "skin", "lesions", "from", "RTRs", "with", "aggressive", "tumors", "for", "p53", "gene", "modifications", ",", "the", "presence", "of", "Human", "Papillomas", "Virus", "(", "HPV", ")", "DNA", "in", "relation", "to", "the", "p53", "codon", "72", "genotype", "and", "polymorphisms", "of", "the", "XPD", "repair", "gene", ".", "We", "detected", "24", "p53", "mutations", "in", "15/25", "(", "60", "%", ")", "NMSCs", ",", "1", "deletion", "and", "23", "base", "substitutions", ",", "the", "majority", "(", "78", "%", ")", "being", "UV-specific", "C", "to", "T", "transitions", "at", "bipyrimidine", "sites", ".", "Importantly", ",", "35", "%", "(", "6/17", ")", "are", "tandem", "mutations", ",", "including", "4", "UV", "signature", "CC", "to", "TT", "transitions", "possibly", "linked", "to", "modulated", "DNA", "repair", "caused", "by", "the", "immunosuppressive", "drug", "cyclosporin", "A", "(", "CsA", ")", ".", "We", "found", "8", "p53", "mutations", "in", "7/17", "(", "41", "%", ")", "precancerous", "actinic", "keratosis", "(", "AK", ")", ",", "suggesting", "that", "p53", "mutations", "are", "early", "events", "in", "RTR", "skin", "carcinogenesis", ".", "Immunohistochemical", "analysis", "shows", "a", "good", "correlation", "between", "p53", "accumulation", "and", "mutations", ".", "HPV", "DNA", "was", "detected", "in", "78", "%", "of", "skin", "lesions", "(", "60", "%", "Basal", "Cell", "Carcinomas", ",", "82", "%", "AK", "and", "79", "%", "SCCs", ")", ".", "Thus", ",", "immunosuppression", "has", "increased", "the", "risk", "of", "infections", "by", "HPVs", ",", "predominantly", "epidermodysplasia", "verruciformis", ",", "speculated", "to", "play", "a", "role", "in", "skin", "cancer", "development", ".", "No", "association", "is", "found", "between", "HPV", "status", "and", "p53", "mutation", ".", "Moreover", ",", "p53", "codon", "72", "or", "frequencies", "of", "three", "XPD", "genotypes", "of", "RTRs", "are", "comparable", "with", "control", "populations", ".", "The", "p53", "mutation", "spectrum", ",", "presenting", "a", "high", "level", "of", "CC", "to", "TT", "mutations", ",", "shows", "that", "the", "UV", "component", "of", "sunlight", "is", "the", "major", "risk", "factor", "and", "modulated", "DNA", "repair", "by", "immunosuppressive", "drug", "treatment", "may", "be", "significant", "in", "the", "skin", "carcinogenesis", "of", "RTRs", "." ]
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17344330
Syncope and QT prolongation among patients treated with methadone for heroin dependence in the city of Copenhagen. BACKGROUND: Methadone is prescribed to heroin addicts to decrease illicit opioid use. Prolongation of the QT interval in the ECG of patients with torsade de pointes (TdP) has been reported in methadone users. As heroin addicts sometimes faint while using illicit drugs, doctors might attribute too many episodes of syncope to illicit drug use and thereby underestimate the incidence of TdP in this special population, and the high mortality in this population may, in part, be caused by the proarrhythmic effect of methadone. METHODS: In this cross-sectional study interview, ECGs and blood samples were collected in a population of adult heroin addicts treated with methadone or buprenorphine on a daily basis. Of the patients at the Drug Addiction Service in the municipal of Copenhagen, 450 (approximately 52%) were included. The QT interval was estimated from 12 lead ECGs. All participants were interviewed about any experience of syncope. The association between opioid dose and QT, and methadone dose and reporting of syncope was assessed using multivariate linear regression and logistic regression, respectively. RESULTS: Methadone dose was associated with longer QT interval of 0.140 ms/mg (p = 0.002). No association between buprenorphine and QTc was found. Among the subjects treated with methadone, 28% men and 32% women had prolonged QTc interval. None of the subjects treated with buprenorphine had QTc interval >0.440 s((1/2)). A 50 mg higher methadone dose was associated with a 1.2 (95% CI 1.1 to 1.4) times higher odds for syncope. CONCLUSIONS: Methadone is associated with QT prolongation and higher reporting of syncope in a population of heroin addicts.
[ "Syncope", "and", "QT", "prolongation", "among", "patients", "treated", "with", "methadone", "for", "heroin", "dependence", "in", "the", "city", "of", "Copenhagen", ".", "BACKGROUND", ":", "Methadone", "is", "prescribed", "to", "heroin", "addicts", "to", "decrease", "illicit", "opioid", "use", ".", "Prolongation", "of", "the", "QT", "interval", "in", "the", "ECG", "of", "patients", "with", "torsade", "de", "pointes", "(", "TdP", ")", "has", "been", "reported", "in", "methadone", "users", ".", "As", "heroin", "addicts", "sometimes", "faint", "while", "using", "illicit", "drugs", ",", "doctors", "might", "attribute", "too", "many", "episodes", "of", "syncope", "to", "illicit", "drug", "use", "and", "thereby", "underestimate", "the", "incidence", "of", "TdP", "in", "this", "special", "population", ",", "and", "the", "high", "mortality", "in", "this", "population", "may", ",", "in", "part", ",", "be", "caused", "by", "the", "proarrhythmic", "effect", "of", "methadone", ".", "METHODS", ":", "In", "this", "cross-sectional", "study", "interview", ",", "ECGs", "and", "blood", "samples", "were", "collected", "in", "a", "population", "of", "adult", "heroin", "addicts", "treated", "with", "methadone", "or", "buprenorphine", "on", "a", "daily", "basis", ".", "Of", "the", "patients", "at", "the", "Drug", "Addiction", "Service", "in", "the", "municipal", "of", "Copenhagen", ",", "450", "(", "approximately", "52", "%", ")", "were", "included", ".", "The", "QT", "interval", "was", "estimated", "from", "12", "lead", "ECGs", ".", "All", "participants", "were", "interviewed", "about", "any", "experience", "of", "syncope", ".", "The", "association", "between", "opioid", "dose", "and", "QT", ",", "and", "methadone", "dose", "and", "reporting", "of", "syncope", "was", "assessed", "using", "multivariate", "linear", "regression", "and", "logistic", "regression", ",", "respectively", ".", "RESULTS", ":", "Methadone", "dose", "was", "associated", "with", "longer", "QT", "interval", "of", "0.140", "ms/mg", "(", "p", "=", "0.002", ")", ".", "No", "association", "between", "buprenorphine", "and", "QTc", "was", "found", ".", "Among", "the", "subjects", "treated", "with", "methadone", ",", "28", "%", "men", "and", "32", "%", "women", "had", "prolonged", "QTc", "interval", ".", "None", "of", "the", "subjects", "treated", "with", "buprenorphine", "had", "QTc", "interval", ">", "0.440", "s", "(", "(", "1/2", ")", ")", ".", "A", "50", "mg", "higher", "methadone", "dose", "was", "associated", "with", "a", "1.2", "(", "95", "%", "CI", "1.1", "to", "1.4", ")", "times", "higher", "odds", "for", "syncope", ".", "CONCLUSIONS", ":", "Methadone", "is", "associated", "with", "QT", "prolongation", "and", "higher", "reporting", "of", "syncope", "in", "a", "population", "of", "heroin", "addicts", "." ]
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18945288
R58fs mutation in the HGD gene in a family with alkaptonuria in the UAE. This study was conducted to determine the prevalence of alkaptonuria in the UAE population and to identify the genotype of affected individuals. In a 3 stage sampling technique 2981 pupils from Government schools in Al Ain and private schools in Dubai were selected to take part in the study, of whom 2857 provided urine samples. Urine collected was analysed for homogentisic acid by gas chromatography-mass spectrometry. Genomic DNA was isolated from the white blood cells of all family members of the affected case following standard established protocols. Specific PRC primers were designed to amplify all 14 exons of the HGD gene with the flanking intronic sequences including the splice site sequences. 2857 children returned a viable urine sample, of which one was highly positive for homogentisic acid. All 12 members of this girl's family were studied and one, a 22 year old brother, was found to excrete HGA. Another, a sister who had not provided a urine sample, was discovered by genetic testing. There were no complaints of joint pain or other symptoms in any member of this family. Parents were first cousins. We found a single nucleotide deletion c.342delA, located in exon 3, which resulted in a frameshift at amino acid position 58 (p.Arg58fs or p.R58fs). Alkaptonuria may be more common than it is thought to be with an allele prevalence estimated at 0.0107 (95% CI 0.000392-0.03473). The R58fs mutation is old, perhaps having occurred several thousand years ago, and has spread over a large geographical area.
[ "R58fs", "mutation", "in", "the", "HGD", "gene", "in", "a", "family", "with", "alkaptonuria", "in", "the", "UAE", ".", "This", "study", "was", "conducted", "to", "determine", "the", "prevalence", "of", "alkaptonuria", "in", "the", "UAE", "population", "and", "to", "identify", "the", "genotype", "of", "affected", "individuals", ".", "In", "a", "3", "stage", "sampling", "technique", "2981", "pupils", "from", "Government", "schools", "in", "Al", "Ain", "and", "private", "schools", "in", "Dubai", "were", "selected", "to", "take", "part", "in", "the", "study", ",", "of", "whom", "2857", "provided", "urine", "samples", ".", "Urine", "collected", "was", "analysed", "for", "homogentisic", "acid", "by", "gas", "chromatography-mass", "spectrometry", ".", "Genomic", "DNA", "was", "isolated", "from", "the", "white", "blood", "cells", "of", "all", "family", "members", "of", "the", "affected", "case", "following", "standard", "established", "protocols", ".", "Specific", "PRC", "primers", "were", "designed", "to", "amplify", "all", "14", "exons", "of", "the", "HGD", "gene", "with", "the", "flanking", "intronic", "sequences", "including", "the", "splice", "site", "sequences", ".", "2857", "children", "returned", "a", "viable", "urine", "sample", ",", "of", "which", "one", "was", "highly", "positive", "for", "homogentisic", "acid", ".", "All", "12", "members", "of", "this", "girl", "'s", "family", "were", "studied", "and", "one", ",", "a", "22", "year", "old", "brother", ",", "was", "found", "to", "excrete", "HGA", ".", "Another", ",", "a", "sister", "who", "had", "not", "provided", "a", "urine", "sample", ",", "was", "discovered", "by", "genetic", "testing", ".", "There", "were", "no", "complaints", "of", "joint", "pain", "or", "other", "symptoms", "in", "any", "member", "of", "this", "family", ".", "Parents", "were", "first", "cousins", ".", "We", "found", "a", "single", "nucleotide", "deletion", "c.342delA", ",", "located", "in", "exon", "3", ",", "which", "resulted", "in", "a", "frameshift", "at", "amino", "acid", "position", "58", "(", "p.Arg58fs", "or", "p.R58fs", ")", ".", "Alkaptonuria", "may", "be", "more", "common", "than", "it", "is", "thought", "to", "be", "with", "an", "allele", "prevalence", "estimated", "at", "0.0107", "(", "95", "%", "CI", "0.000392-0.03473", ")", ".", "The", "R58fs", "mutation", "is", "old", ",", "perhaps", "having", "occurred", "several", "thousand", "years", "ago", ",", "and", "has", "spread", "over", "a", "large", "geographical", "area", "." ]
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20080916
Promoter insertion/deletion in the IRF5 gene is highly associated with susceptibility to systemic lupus erythematosus in distinct populations, but exerts a modest effect on gene expression in peripheral blood mononuclear cells. OBJECTIVE: We examined the genetic association of the promoter insertion/deletion (indel) in IRF5 gene with systemic lupus erythematosus (SLE) in distinct populations and assessed its role in gene expression. METHODS: Four IRF5 polymorphisms were genotyped in 1488 SLE patients and 1466 controls. Gene expression was analyzed by quantitative real-time PCR using RNA from peripheral blood mononuclear cells (PBMC). RESULTS: The promoter indel and rs2070197 had independent genetic effects, which accounted for the association of rs2004640 and rs10954213. Gene expression analysis revealed that rs10954213 exerted the greatest influence on IRF5 transcript levels. CONCLUSION: We corroborated the association of the promoter indel with SLE in 5 different populations and revealed that rs10954213 is the main single-nucleotide polymorphism responsible for altered IRF5 expression in PBMC.
[ "Promoter", "insertion/deletion", "in", "the", "IRF5", "gene", "is", "highly", "associated", "with", "susceptibility", "to", "systemic", "lupus", "erythematosus", "in", "distinct", "populations", ",", "but", "exerts", "a", "modest", "effect", "on", "gene", "expression", "in", "peripheral", "blood", "mononuclear", "cells", ".", "OBJECTIVE", ":", "We", "examined", "the", "genetic", "association", "of", "the", "promoter", "insertion/deletion", "(", "indel", ")", "in", "IRF5", "gene", "with", "systemic", "lupus", "erythematosus", "(", "SLE", ")", "in", "distinct", "populations", "and", "assessed", "its", "role", "in", "gene", "expression", ".", "METHODS", ":", "Four", "IRF5", "polymorphisms", "were", "genotyped", "in", "1488", "SLE", "patients", "and", "1466", "controls", ".", "Gene", "expression", "was", "analyzed", "by", "quantitative", "real-time", "PCR", "using", "RNA", "from", "peripheral", "blood", "mononuclear", "cells", "(", "PBMC", ")", ".", "RESULTS", ":", "The", "promoter", "indel", "and", "rs2070197", "had", "independent", "genetic", "effects", ",", "which", "accounted", "for", "the", "association", "of", "rs2004640", "and", "rs10954213", ".", "Gene", "expression", "analysis", "revealed", "that", "rs10954213", "exerted", "the", "greatest", "influence", "on", "IRF5", "transcript", "levels", ".", "CONCLUSION", ":", "We", "corroborated", "the", "association", "of", "the", "promoter", "indel", "with", "SLE", "in", "5", "different", "populations", "and", "revealed", "that", "rs10954213", "is", "the", "main", "single-nucleotide", "polymorphism", "responsible", "for", "altered", "IRF5", "expression", "in", "PBMC", "." ]
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15649253
Primary malignant lymphoma of the brain: frequent abnormalities and inactivation of p14 tumor suppressor gene. Ten primary central nervous system lymphomas (PCNSL, brain lymphomas) were examined for p14 gene exon 1beta deletion, mutation and methylation by Southern blot analysis, nucleotide analysis of polymerase chain reaction clones and Southern blot-based methylation assay. In Southern blot analysis, from the signal densities of the hybridized bands and their similarities to those of exons 2 and 3 in our previous quantitative study, we found that exon 1beta was homozygously deleted in four cases, hemizygously deleted in five cases and not deleted in one case. Thus, the same deletion patterns covered the entire p14 gene for all cases except for one case, which suggested the hemizygous deletion of exons 1beta and 2 and homozygous deletion of exon 3. In addition, although exon 1beta mutation is rare in various tumors, we detected a missense mutation (L50R) in one case with a hemizygous deletion. Methylation of the 5'CpG island of the p14 gene was not suggested for any case without homozygous deletion. Our observation of frequent p14 gene abnormalities (90%) and inactivation (40-60%) was in striking contrast to the same pathological subtype of systemic lymphoma in which p14 gene abnormalities and inactivation were infrequent, suggesting a difference in carcinogenesis between PCNSL and systemic lymphoma.
[ "Primary", "malignant", "lymphoma", "of", "the", "brain", ":", "frequent", "abnormalities", "and", "inactivation", "of", "p14", "tumor", "suppressor", "gene", ".", "Ten", "primary", "central", "nervous", "system", "lymphomas", "(", "PCNSL", ",", "brain", "lymphomas", ")", "were", "examined", "for", "p14", "gene", "exon", "1beta", "deletion", ",", "mutation", "and", "methylation", "by", "Southern", "blot", "analysis", ",", "nucleotide", "analysis", "of", "polymerase", "chain", "reaction", "clones", "and", "Southern", "blot-based", "methylation", "assay", ".", "In", "Southern", "blot", "analysis", ",", "from", "the", "signal", "densities", "of", "the", "hybridized", "bands", "and", "their", "similarities", "to", "those", "of", "exons", "2", "and", "3", "in", "our", "previous", "quantitative", "study", ",", "we", "found", "that", "exon", "1beta", "was", "homozygously", "deleted", "in", "four", "cases", ",", "hemizygously", "deleted", "in", "five", "cases", "and", "not", "deleted", "in", "one", "case", ".", "Thus", ",", "the", "same", "deletion", "patterns", "covered", "the", "entire", "p14", "gene", "for", "all", "cases", "except", "for", "one", "case", ",", "which", "suggested", "the", "hemizygous", "deletion", "of", "exons", "1beta", "and", "2", "and", "homozygous", "deletion", "of", "exon", "3", ".", "In", "addition", ",", "although", "exon", "1beta", "mutation", "is", "rare", "in", "various", "tumors", ",", "we", "detected", "a", "missense", "mutation", "(", "L50R", ")", "in", "one", "case", "with", "a", "hemizygous", "deletion", ".", "Methylation", "of", "the", "5'CpG", "island", "of", "the", "p14", "gene", "was", "not", "suggested", "for", "any", "case", "without", "homozygous", "deletion", ".", "Our", "observation", "of", "frequent", "p14", "gene", "abnormalities", "(", "90", "%", ")", "and", "inactivation", "(", "40-60", "%", ")", "was", "in", "striking", "contrast", "to", "the", "same", "pathological", "subtype", "of", "systemic", "lymphoma", "in", "which", "p14", "gene", "abnormalities", "and", "inactivation", "were", "infrequent", ",", "suggesting", "a", "difference", "in", "carcinogenesis", "between", "PCNSL", "and", "systemic", "lymphoma", "." ]
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16321363
Congenital disorder of glycosylation Ic due to a de novo deletion and an hALG-6 mutation. We describe a new cause of congenital disorder of glycosylation-Ic (CDG-Ic) in a young girl with a rather mild CDG phenotype. Her cells accumulated lipid-linked oligosaccharides lacking three glucose residues, and sequencing of the ALG6 gene showed what initially appeared to be a homozygous novel point mutation (338G>A). However, haplotype analysis showed that the patient does not carry any paternal DNA markers extending 33kb in the telomeric direction from the ALG6 region, and microsatellite analysis extended the abnormal region to at least 2.5Mb. We used high-resolution karyotyping to confirm a deletion (10-12Mb) [del(1)(p31.2p32.3)] and found no structural abnormalities in the father, suggesting a de novo event. Our findings extend the causes of CDG to larger DNA deletions and identify the first Japanese CDG-Ic mutation.
[ "Congenital", "disorder", "of", "glycosylation", "Ic", "due", "to", "a", "de", "novo", "deletion", "and", "an", "hALG-6", "mutation", ".", "We", "describe", "a", "new", "cause", "of", "congenital", "disorder", "of", "glycosylation-Ic", "(", "CDG-Ic", ")", "in", "a", "young", "girl", "with", "a", "rather", "mild", "CDG", "phenotype", ".", "Her", "cells", "accumulated", "lipid-linked", "oligosaccharides", "lacking", "three", "glucose", "residues", ",", "and", "sequencing", "of", "the", "ALG6", "gene", "showed", "what", "initially", "appeared", "to", "be", "a", "homozygous", "novel", "point", "mutation", "(", "338G", ">", "A", ")", ".", "However", ",", "haplotype", "analysis", "showed", "that", "the", "patient", "does", "not", "carry", "any", "paternal", "DNA", "markers", "extending", "33kb", "in", "the", "telomeric", "direction", "from", "the", "ALG6", "region", ",", "and", "microsatellite", "analysis", "extended", "the", "abnormal", "region", "to", "at", "least", "2.5Mb", ".", "We", "used", "high-resolution", "karyotyping", "to", "confirm", "a", "deletion", "(", "10-12Mb", ")", "[", "del", "(", "1", ")", "(", "p31.2p32.3", ")", "]", "and", "found", "no", "structural", "abnormalities", "in", "the", "father", ",", "suggesting", "a", "de", "novo", "event", ".", "Our", "findings", "extend", "the", "causes", "of", "CDG", "to", "larger", "DNA", "deletions", "and", "identify", "the", "first", "Japanese", "CDG-Ic", "mutation", "." ]
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16506214
Genetic variation in the COX-2 gene and the association with prostate cancer risk. COX-2 is a key enzyme in the conversion of arachidonic acid to prostaglandins. The prostaglandins produced by COX-2 are involved in inflammation and pain response in different tissues in the body. Accumulating evidence from epidemiologic studies, chemical carcinogen-induced rodent models and clinical trials indicate that COX-2 plays a role in human carcinogenesis and is overexpressed in prostate cancer tissue. We examined whether sequence variants in the COX-2 gene are associated with prostate cancer risk. We analyzed a large population-based case-control study, cancer prostate in Sweden (CAPS) consisting of 1,378 cases and 782 controls. We evaluated 16 single nucleotide polymorphisms (SNPs) spanning the entire COX-2 gene in 94 subjects of the control group. Five SNPs had a minor allele frequency of more than 5% in our study population and these were genotyped in all case patients and control subjects and gene-specific haplotypes were constructed. A statistically significant difference in allele frequency between cases and controls was observed for 2 of the SNPs (+3100 T/G and +8365 C/T), with an odds ratio of 0.78 (95% CI=0.64-0.96) and 0.65 (95% CI=0.45-0.94) respectively. In the haplotype analysis, 1 haplotype carrying the variant allele from both +3100 T/G and +8365 C/T, with a population frequency of 3%, was also significantly associated with decreased risk of prostate cancer (p=0.036, global simulated p-value=0.046). This study supports the hypothesis that inflammation is involved in prostate carcinogenesis and that sequence variation within the COX-2 gene influence the risk of prostate cancer.
[ "Genetic", "variation", "in", "the", "COX-2", "gene", "and", "the", "association", "with", "prostate", "cancer", "risk", ".", "COX-2", "is", "a", "key", "enzyme", "in", "the", "conversion", "of", "arachidonic", "acid", "to", "prostaglandins", ".", "The", "prostaglandins", "produced", "by", "COX-2", "are", "involved", "in", "inflammation", "and", "pain", "response", "in", "different", "tissues", "in", "the", "body", ".", "Accumulating", "evidence", "from", "epidemiologic", "studies", ",", "chemical", "carcinogen-induced", "rodent", "models", "and", "clinical", "trials", "indicate", "that", "COX-2", "plays", "a", "role", "in", "human", "carcinogenesis", "and", "is", "overexpressed", "in", "prostate", "cancer", "tissue", ".", "We", "examined", "whether", "sequence", "variants", "in", "the", "COX-2", "gene", "are", "associated", "with", "prostate", "cancer", "risk", ".", "We", "analyzed", "a", "large", "population-based", "case-control", "study", ",", "cancer", "prostate", "in", "Sweden", "(", "CAPS", ")", "consisting", "of", "1,378", "cases", "and", "782", "controls", ".", "We", "evaluated", "16", "single", "nucleotide", "polymorphisms", "(", "SNPs", ")", "spanning", "the", "entire", "COX-2", "gene", "in", "94", "subjects", "of", "the", "control", "group", ".", "Five", "SNPs", "had", "a", "minor", "allele", "frequency", "of", "more", "than", "5", "%", "in", "our", "study", "population", "and", "these", "were", "genotyped", "in", "all", "case", "patients", "and", "control", "subjects", "and", "gene-specific", "haplotypes", "were", "constructed", ".", "A", "statistically", "significant", "difference", "in", "allele", "frequency", "between", "cases", "and", "controls", "was", "observed", "for", "2", "of", "the", "SNPs", "(", "+3100", "T/G", "and", "+8365", "C/T", ")", ",", "with", "an", "odds", "ratio", "of", "0.78", "(", "95", "%", "CI=0.64-0.96", ")", "and", "0.65", "(", "95", "%", "CI=0.45-0.94", ")", "respectively", ".", "In", "the", "haplotype", "analysis", ",", "1", "haplotype", "carrying", "the", "variant", "allele", "from", "both", "+3100", "T/G", "and", "+8365", "C/T", ",", "with", "a", "population", "frequency", "of", "3", "%", ",", "was", "also", "significantly", "associated", "with", "decreased", "risk", "of", "prostate", "cancer", "(", "p=0.036", ",", "global", "simulated", "p-value=0.046", ")", ".", "This", "study", "supports", "the", "hypothesis", "that", "inflammation", "is", "involved", "in", "prostate", "carcinogenesis", "and", "that", "sequence", "variation", "within", "the", "COX-2", "gene", "influence", "the", "risk", "of", "prostate", "cancer", "." ]
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16801510
Drug-induced long QT syndrome in injection drug users receiving methadone: high frequency in hospitalized patients and risk factors. BACKGROUND: Drug-induced long QT syndrome is a serious adverse drug reaction. Methadone prolongs the QT interval in vitro in a dose-dependent manner. In the inpatient setting, the frequency of QT interval prolongation with methadone treatment, its dose dependence, and the importance of cofactors such as drug-drug interactions remain unknown. METHODS: We performed a systematic, retrospective study comparing active or former intravenous drug users receiving methadone and those not receiving methadone among all patients hospitalized over a 5-year period in a tertiary care hospital. A total of 167 patients receiving methadone fulfilled the inclusion criteria and were compared with a control group of 80 injection drug users not receiving methadone. In addition to methadone dose, 15 demographic, biological, and pharmacological variables were considered as potential risk factors for QT prolongation. RESULTS: Among 167 methadone maintenance patients, the prevalence of QTc prolongation to 0.50 second((1/2)) or longer was 16.2% compared with 0% in 80 control subjects. Six patients (3.6%) in the methadone group presented torsades de pointes. QTc length was weakly but significantly associated with methadone daily dose (Spearman rank correlation coefficient, 0.20; P<.01). Multivariate regression analysis allowed attribution of 31.8% of QTc variability to methadone dose, cytochrome P-450 3A4 drug-drug interactions, hypokalemia, and altered liver function. CONCLUSIONS: QT interval prolongation in methadone maintenance patients hospitalized in a tertiary care center is a frequent finding. Methadone dose, presence of cytochrome P-450 3A4 inhibitors, potassium level, and liver function contribute to QT prolongation. Long QT syndrome can occur with low doses of methadone.
[ "Drug-induced", "long", "QT", "syndrome", "in", "injection", "drug", "users", "receiving", "methadone", ":", "high", "frequency", "in", "hospitalized", "patients", "and", "risk", "factors", ".", "BACKGROUND", ":", "Drug-induced", "long", "QT", "syndrome", "is", "a", "serious", "adverse", "drug", "reaction", ".", "Methadone", "prolongs", "the", "QT", "interval", "in", "vitro", "in", "a", "dose-dependent", "manner", ".", "In", "the", "inpatient", "setting", ",", "the", "frequency", "of", "QT", "interval", "prolongation", "with", "methadone", "treatment", ",", "its", "dose", "dependence", ",", "and", "the", "importance", "of", "cofactors", "such", "as", "drug-drug", "interactions", "remain", "unknown", ".", "METHODS", ":", "We", "performed", "a", "systematic", ",", "retrospective", "study", "comparing", "active", "or", "former", "intravenous", "drug", "users", "receiving", "methadone", "and", "those", "not", "receiving", "methadone", "among", "all", "patients", "hospitalized", "over", "a", "5-year", "period", "in", "a", "tertiary", "care", "hospital", ".", "A", "total", "of", "167", "patients", "receiving", "methadone", "fulfilled", "the", "inclusion", "criteria", "and", "were", "compared", "with", "a", "control", "group", "of", "80", "injection", "drug", "users", "not", "receiving", "methadone", ".", "In", "addition", "to", "methadone", "dose", ",", "15", "demographic", ",", "biological", ",", "and", "pharmacological", "variables", "were", "considered", "as", "potential", "risk", "factors", "for", "QT", "prolongation", ".", "RESULTS", ":", "Among", "167", "methadone", "maintenance", "patients", ",", "the", "prevalence", "of", "QTc", "prolongation", "to", "0.50", "second", "(", "(", "1/2", ")", ")", "or", "longer", "was", "16.2", "%", "compared", "with", "0", "%", "in", "80", "control", "subjects", ".", "Six", "patients", "(", "3.6", "%", ")", "in", "the", "methadone", "group", "presented", "torsades", "de", "pointes", ".", "QTc", "length", "was", "weakly", "but", "significantly", "associated", "with", "methadone", "daily", "dose", "(", "Spearman", "rank", "correlation", "coefficient", ",", "0.20", ";", "P", "<", ".01", ")", ".", "Multivariate", "regression", "analysis", "allowed", "attribution", "of", "31.8", "%", "of", "QTc", "variability", "to", "methadone", "dose", ",", "cytochrome", "P-450", "3A4", "drug-drug", "interactions", ",", "hypokalemia", ",", "and", "altered", "liver", "function", ".", "CONCLUSIONS", ":", "QT", "interval", "prolongation", "in", "methadone", "maintenance", "patients", "hospitalized", "in", "a", "tertiary", "care", "center", "is", "a", "frequent", "finding", ".", "Methadone", "dose", ",", "presence", "of", "cytochrome", "P-450", "3A4", "inhibitors", ",", "potassium", "level", ",", "and", "liver", "function", "contribute", "to", "QT", "prolongation", ".", "Long", "QT", "syndrome", "can", "occur", "with", "low", "doses", "of", "methadone", "." ]
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18809400
Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy. The study investigates if alpha-lipoic acid is neuroprotective against chemotherapy induced neurotoxicity, if mitochondrial damage plays a critical role in toxic neurodegenerative cascade, and if neuroprotective effects of alpha-lipoic acid depend on mitochondria protection. We used an in vitro model of chemotherapy induced peripheral neuropathy that closely mimic the in vivo condition by exposing primary cultures of dorsal root ganglion (DRG) sensory neurons to paclitaxel and cisplatin, two widely used and highly effective chemotherapeutic drugs. This approach allowed investigating the efficacy of alpha-lipoic acid in preventing axonal damage and apoptosis and the function and ultrastructural morphology of mitochondria after exposure to toxic agents and alpha-lipoic acid. Our results demonstrate that both cisplatin and paclitaxel cause early mitochondrial impairment with loss of membrane potential and induction of autophagic vacuoles in neurons. Alpha-lipoic acid exerts neuroprotective effects against chemotherapy induced neurotoxicity in sensory neurons: it rescues the mitochondrial toxicity and induces the expression of frataxin, an essential mitochondrial protein with anti-oxidant and chaperone properties. In conclusion mitochondrial toxicity is an early common event both in paclitaxel and cisplatin induced neurotoxicity. Alpha-lipoic acid protects sensory neurons through its anti-oxidant and mitochondrial regulatory functions, possibly inducing the expression of frataxin. These findings suggest that alpha-lipoic acid might reduce the risk of developing peripheral nerve toxicity in patients undergoing chemotherapy and encourage further confirmatory clinical trials.
[ "Alpha-lipoic", "acid", "prevents", "mitochondrial", "damage", "and", "neurotoxicity", "in", "experimental", "chemotherapy", "neuropathy", ".", "The", "study", "investigates", "if", "alpha-lipoic", "acid", "is", "neuroprotective", "against", "chemotherapy", "induced", "neurotoxicity", ",", "if", "mitochondrial", "damage", "plays", "a", "critical", "role", "in", "toxic", "neurodegenerative", "cascade", ",", "and", "if", "neuroprotective", "effects", "of", "alpha-lipoic", "acid", "depend", "on", "mitochondria", "protection", ".", "We", "used", "an", "in", "vitro", "model", "of", "chemotherapy", "induced", "peripheral", "neuropathy", "that", "closely", "mimic", "the", "in", "vivo", "condition", "by", "exposing", "primary", "cultures", "of", "dorsal", "root", "ganglion", "(", "DRG", ")", "sensory", "neurons", "to", "paclitaxel", "and", "cisplatin", ",", "two", "widely", "used", "and", "highly", "effective", "chemotherapeutic", "drugs", ".", "This", "approach", "allowed", "investigating", "the", "efficacy", "of", "alpha-lipoic", "acid", "in", "preventing", "axonal", "damage", "and", "apoptosis", "and", "the", "function", "and", "ultrastructural", "morphology", "of", "mitochondria", "after", "exposure", "to", "toxic", "agents", "and", "alpha-lipoic", "acid", ".", "Our", "results", "demonstrate", "that", "both", "cisplatin", "and", "paclitaxel", "cause", "early", "mitochondrial", "impairment", "with", "loss", "of", "membrane", "potential", "and", "induction", "of", "autophagic", "vacuoles", "in", "neurons", ".", "Alpha-lipoic", "acid", "exerts", "neuroprotective", "effects", "against", "chemotherapy", "induced", "neurotoxicity", "in", "sensory", "neurons", ":", "it", "rescues", "the", "mitochondrial", "toxicity", "and", "induces", "the", "expression", "of", "frataxin", ",", "an", "essential", "mitochondrial", "protein", "with", "anti-oxidant", "and", "chaperone", "properties", ".", "In", "conclusion", "mitochondrial", "toxicity", "is", "an", "early", "common", "event", "both", "in", "paclitaxel", "and", "cisplatin", "induced", "neurotoxicity", ".", "Alpha-lipoic", "acid", "protects", "sensory", "neurons", "through", "its", "anti-oxidant", "and", "mitochondrial", "regulatory", "functions", ",", "possibly", "inducing", "the", "expression", "of", "frataxin", ".", "These", "findings", "suggest", "that", "alpha-lipoic", "acid", "might", "reduce", "the", "risk", "of", "developing", "peripheral", "nerve", "toxicity", "in", "patients", "undergoing", "chemotherapy", "and", "encourage", "further", "confirmatory", "clinical", "trials", "." ]
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27860244
Role of protein arginine methyltransferase 5 in inflammation and migration of fibroblast-like synoviocytes in rheumatoid arthritis. To probe the role of protein arginine methyltransferase 5 (PRMT5) in regulating inflammation, cell proliferation, migration and invasion of fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA). FLSs were separated from synovial tissues (STs) from patients with RA and osteoarthritis (OA). An inhibitor of PRMT5 (EPZ015666) and short interference RNA (siRNA) against PRMT5 were used to inhibit PRMT5 expression. The standard of protein was measured by Western blot or immunofluorescence. The excretion and genetic expression of inflammatory factors were, respectively, estimated by enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR). Migration and invasion in vitro were detected by Boyden chamber assay. FLSs proliferation was detected by BrdU incorporation. Increased PRMT5 was discovered in STs and FLSs from patients with RA. In RA FLSs, the level of PRMT5 was up-regulated by stimulation with IL-1b and TNF-a. Inhibition of PRMT5 by EPZ015666 and siRNA-mediated knockdown reduced IL-6 and IL-8 production, and proliferation of RA FLSs. In addition, inhibition of PRMT5 decreased in vitro migration and invasion of RA FLSs. Furthermore, EPZ015666 restrained the phosphorylation of IkB kinaseb and IkBa, as well as nucleus transsituation of p65 as well as AKT in FLSs. PRMT5 regulated the production of inflammatory factors, cell proliferation, migration and invasion of RA FLS, which was mediated by the NF-kB and AKT pathways. Our data suggested that targeting PRMT5 to prevent synovial inflammation and destruction might be a promising therapy for RA.
[ "Role", "of", "protein", "arginine", "methyltransferase", "5", "in", "inflammation", "and", "migration", "of", "fibroblast-like", "synoviocytes", "in", "rheumatoid", "arthritis", ".", "To", "probe", "the", "role", "of", "protein", "arginine", "methyltransferase", "5", "(", "PRMT5", ")", "in", "regulating", "inflammation", ",", "cell", "proliferation", ",", "migration", "and", "invasion", "of", "fibroblast-like", "synoviocytes", "(", "FLSs", ")", "from", "patients", "with", "rheumatoid", "arthritis", "(", "RA", ")", ".", "FLSs", "were", "separated", "from", "synovial", "tissues", "(", "STs", ")", "from", "patients", "with", "RA", "and", "osteoarthritis", "(", "OA", ")", ".", "An", "inhibitor", "of", "PRMT5", "(", "EPZ015666", ")", "and", "short", "interference", "RNA", "(", "siRNA", ")", "against", "PRMT5", "were", "used", "to", "inhibit", "PRMT5", "expression", ".", "The", "standard", "of", "protein", "was", "measured", "by", "Western", "blot", "or", "immunofluorescence", ".", "The", "excretion", "and", "genetic", "expression", "of", "inflammatory", "factors", "were", ",", "respectively", ",", "estimated", "by", "enzyme-linked", "immunosorbent", "assay", "(", "ELISA", ")", "and", "real-time", "polymerase", "chain", "reaction", "(", "PCR", ")", ".", "Migration", "and", "invasion", "in", "vitro", "were", "detected", "by", "Boyden", "chamber", "assay", ".", "FLSs", "proliferation", "was", "detected", "by", "BrdU", "incorporation", ".", "Increased", "PRMT5", "was", "discovered", "in", "STs", "and", "FLSs", "from", "patients", "with", "RA", ".", "In", "RA", "FLSs", ",", "the", "level", "of", "PRMT5", "was", "up-regulated", "by", "stimulation", "with", "IL-1b", "and", "TNF-a", ".", "Inhibition", "of", "PRMT5", "by", "EPZ015666", "and", "siRNA-mediated", "knockdown", "reduced", "IL-6", "and", "IL-8", "production", ",", "and", "proliferation", "of", "RA", "FLSs", ".", "In", "addition", ",", "inhibition", "of", "PRMT5", "decreased", "in", "vitro", "migration", "and", "invasion", "of", "RA", "FLSs", ".", "Furthermore", ",", "EPZ015666", "restrained", "the", "phosphorylation", "of", "IkB", "kinaseb", "and", "IkBa", ",", "as", "well", "as", "nucleus", "transsituation", "of", "p65", "as", "well", "as", "AKT", "in", "FLSs", ".", "PRMT5", "regulated", "the", "production", "of", "inflammatory", "factors", ",", "cell", "proliferation", ",", "migration", "and", "invasion", "of", "RA", "FLS", ",", "which", "was", "mediated", "by", "the", "NF-kB", "and", "AKT", "pathways", ".", "Our", "data", "suggested", "that", "targeting", "PRMT5", "to", "prevent", "synovial", "inflammation", "and", "destruction", "might", "be", "a", "promising", "therapy", "for", "RA", "." ]
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15064320
Compound heterozygous mutations in the SRD5A2 gene exon 4 in a male pseudohermaphrodite patient of Chinese origin. The goal of this study was to perform 5-alpha-reductase type 2 gene (SRD5A2) analysis in a male pseudohermaphrodite (MPH) patient with normal testosterone (T) production and normal androgen receptor (AR) gene coding sequences. A patient of Chinese origin with ambiguous genitalia at 14 months, a 46,XY karyotype, and normal T secretion under human chorionic gonadotropin (hCG) stimulation underwent a gonadectomy at 20 months. Exons 1-8 of the AR gene and exons 1-5 of the SRD5A2 gene were sequenced from peripheral blood DNA. AR gene coding sequences were normal. SRD5A2 gene analysis revealed 2 consecutive mutations in exon 4, each located in a different allele: 1) a T nucleotide deletion, which predicts a frameshift mutation from codon 219, and 2) a missense mutation at codon 227, where the substitution of guanine (CGA) by adenine (CAA) predicts a glutamine replacement of arginine (R227Q). Testes located in the inguinal canal showed a normal morphology for age. The patient was a compound heterozygote for SRD5A2 mutations, carrying 2 mutations in exon 4. The patient showed an R227Q mutation that has been described in an Asian population and MPH patients, along with a novel frameshift mutation, Tdel219. Testis morphology showed that, during early infancy, the 5-alpha-reductase enzyme deficiency may not have affected interstitial or tubular development.
[ "Compound", "heterozygous", "mutations", "in", "the", "SRD5A2", "gene", "exon", "4", "in", "a", "male", "pseudohermaphrodite", "patient", "of", "Chinese", "origin", ".", "The", "goal", "of", "this", "study", "was", "to", "perform", "5-alpha-reductase", "type", "2", "gene", "(", "SRD5A2", ")", "analysis", "in", "a", "male", "pseudohermaphrodite", "(", "MPH", ")", "patient", "with", "normal", "testosterone", "(", "T", ")", "production", "and", "normal", "androgen", "receptor", "(", "AR", ")", "gene", "coding", "sequences", ".", "A", "patient", "of", "Chinese", "origin", "with", "ambiguous", "genitalia", "at", "14", "months", ",", "a", "46", ",", "XY", "karyotype", ",", "and", "normal", "T", "secretion", "under", "human", "chorionic", "gonadotropin", "(", "hCG", ")", "stimulation", "underwent", "a", "gonadectomy", "at", "20", "months", ".", "Exons", "1-8", "of", "the", "AR", "gene", "and", "exons", "1-5", "of", "the", "SRD5A2", "gene", "were", "sequenced", "from", "peripheral", "blood", "DNA", ".", "AR", "gene", "coding", "sequences", "were", "normal", ".", "SRD5A2", "gene", "analysis", "revealed", "2", "consecutive", "mutations", "in", "exon", "4", ",", "each", "located", "in", "a", "different", "allele", ":", "1", ")", "a", "T", "nucleotide", "deletion", ",", "which", "predicts", "a", "frameshift", "mutation", "from", "codon", "219", ",", "and", "2", ")", "a", "missense", "mutation", "at", "codon", "227", ",", "where", "the", "substitution", "of", "guanine", "(", "CGA", ")", "by", "adenine", "(", "CAA", ")", "predicts", "a", "glutamine", "replacement", "of", "arginine", "(", "R227Q", ")", ".", "Testes", "located", "in", "the", "inguinal", "canal", "showed", "a", "normal", "morphology", "for", "age", ".", "The", "patient", "was", "a", "compound", "heterozygote", "for", "SRD5A2", "mutations", ",", "carrying", "2", "mutations", "in", "exon", "4", ".", "The", "patient", "showed", "an", "R227Q", "mutation", "that", "has", "been", "described", "in", "an", "Asian", "population", "and", "MPH", "patients", ",", "along", "with", "a", "novel", "frameshift", "mutation", ",", "Tdel219", ".", "Testis", "morphology", "showed", "that", ",", "during", "early", "infancy", ",", "the", "5-alpha-reductase", "enzyme", "deficiency", "may", "not", "have", "affected", "interstitial", "or", "tubular", "development", "." ]
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15623763
TGFBI gene mutations causing lattice and granular corneal dystrophies in Indian patients. PURPOSE: To identify mutations in the TGFBI gene in Indian patients with lattice corneal dystrophy (LCD) or granular corneal dystrophy (GCD) and to look for genotype-phenotype correlations. METHODS: Thirty-seven unrelated patients were studied, 18 with LCD and 19 with GCD. The diagnosis of LCD or GCD was made on the basis of clinical and/or histopathological evaluation. Exons and flanking intron sequences of the TGFBI gene were amplified by PCR with specific primers. PCR products were screened by the method of single-strand conformation polymorphism followed by sequencing. Mutations were confirmed by screening at least 100 unrelated normal control subjects. RESULTS: Mutations were identified in 14 of 18 patients with LCD and in all 19 patients with GCD. In LCD, three novel heterozygous mutations found were glycine-594-valine (Gly594Val) in 2 of 18 patients, valine-539-aspartic acid (Val539Asp) in 1 patient, and deletion of valine 624, valine 625 (Val624-Val625del) in 1 patient. In addition, mutation of arginine 124-to-cysteine (Arg124Cys) was found in 8 of 18 patients and histidine 626-to-arginine (His626Arg) in 2 of 18 patients. Atypical clinical features for LCD were noted in patients with the Gly594Val and Val624-Val625del mutations. In GCD, 18 patients with GCD type I had a mutation of arginine 555-to-tryptophan (Arg555Trp) and 1 patient with GCD type III (Reis-Bucklers dystrophy), had the Arg124Leu mutation. Seven novel single-nucleotide polymorphisms (SNPs) were also found, of which a change of leucine 269 to phenylalanine (Leu269Phe) was found in 12 of 18 patients with the Arg555Trp mutation. CONCLUSIONS: Arg124Cys and Arg555Trp appear to be the predominant mutations causing LCD and GCD, respectively, in the population studied. The novel mutations identified in this study are associated with distinct phenotypes.
[ "TGFBI", "gene", "mutations", "causing", "lattice", "and", "granular", "corneal", "dystrophies", "in", "Indian", "patients", ".", "PURPOSE", ":", "To", "identify", "mutations", "in", "the", "TGFBI", "gene", "in", "Indian", "patients", "with", "lattice", "corneal", "dystrophy", "(", "LCD", ")", "or", "granular", "corneal", "dystrophy", "(", "GCD", ")", "and", "to", "look", "for", "genotype-phenotype", "correlations", ".", "METHODS", ":", "Thirty-seven", "unrelated", "patients", "were", "studied", ",", "18", "with", "LCD", "and", "19", "with", "GCD", ".", "The", "diagnosis", "of", "LCD", "or", "GCD", "was", "made", "on", "the", "basis", "of", "clinical", "and/or", "histopathological", "evaluation", ".", "Exons", "and", "flanking", "intron", "sequences", "of", "the", "TGFBI", "gene", "were", "amplified", "by", "PCR", "with", "specific", "primers", ".", "PCR", "products", "were", "screened", "by", "the", "method", "of", "single-strand", "conformation", "polymorphism", "followed", "by", "sequencing", ".", "Mutations", "were", "confirmed", "by", "screening", "at", "least", "100", "unrelated", "normal", "control", "subjects", ".", "RESULTS", ":", "Mutations", "were", "identified", "in", "14", "of", "18", "patients", "with", "LCD", "and", "in", "all", "19", "patients", "with", "GCD", ".", "In", "LCD", ",", "three", "novel", "heterozygous", "mutations", "found", "were", "glycine-594-valine", "(", "Gly594Val", ")", "in", "2", "of", "18", "patients", ",", "valine-539-aspartic", "acid", "(", "Val539Asp", ")", "in", "1", "patient", ",", "and", "deletion", "of", "valine", "624", ",", "valine", "625", "(", "Val624-Val625del", ")", "in", "1", "patient", ".", "In", "addition", ",", "mutation", "of", "arginine", "124-to-cysteine", "(", "Arg124Cys", ")", "was", "found", "in", "8", "of", "18", "patients", "and", "histidine", "626-to-arginine", "(", "His626Arg", ")", "in", "2", "of", "18", "patients", ".", "Atypical", "clinical", "features", "for", "LCD", "were", "noted", "in", "patients", "with", "the", "Gly594Val", "and", "Val624-Val625del", "mutations", ".", "In", "GCD", ",", "18", "patients", "with", "GCD", "type", "I", "had", "a", "mutation", "of", "arginine", "555-to-tryptophan", "(", "Arg555Trp", ")", "and", "1", "patient", "with", "GCD", "type", "III", "(", "Reis-Bucklers", "dystrophy", ")", ",", "had", "the", "Arg124Leu", "mutation", ".", "Seven", "novel", "single-nucleotide", "polymorphisms", "(", "SNPs", ")", "were", "also", "found", ",", "of", "which", "a", "change", "of", "leucine", "269", "to", "phenylalanine", "(", "Leu269Phe", ")", "was", "found", "in", "12", "of", "18", "patients", "with", "the", "Arg555Trp", "mutation", ".", "CONCLUSIONS", ":", "Arg124Cys", "and", "Arg555Trp", "appear", "to", "be", "the", "predominant", "mutations", "causing", "LCD", "and", "GCD", ",", "respectively", ",", "in", "the", "population", "studied", ".", "The", "novel", "mutations", "identified", "in", "this", "study", "are", "associated", "with", "distinct", "phenotypes", "." ]
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17639754
Interaction between warfarin and levofloxacin: case series. Warfarin is the most widely used oral anticoagulant and is indicated for many clinical conditions. Levofloxacin, a fluoroquinolone, is one of the most commonly prescribed antibiotics in clinical practice and is effective against Gram-positive, Gram-negative, and atypical bacteria. While small prospective studies have not revealed any significant drug-drug interaction between warfarin and levofloxacin, several case reports have indicated that levofloxacin may significantly potentiate the anticoagulation effect of warfarin. We report 3 cases of serious bleeding complications that appear to be the result of the interaction between warfarin and levofloxacin. Physicians should be aware of this potential interaction and use caution when prescribing levofloxacin to patients taking warfarin.
[ "Interaction", "between", "warfarin", "and", "levofloxacin", ":", "case", "series", ".", "Warfarin", "is", "the", "most", "widely", "used", "oral", "anticoagulant", "and", "is", "indicated", "for", "many", "clinical", "conditions", ".", "Levofloxacin", ",", "a", "fluoroquinolone", ",", "is", "one", "of", "the", "most", "commonly", "prescribed", "antibiotics", "in", "clinical", "practice", "and", "is", "effective", "against", "Gram-positive", ",", "Gram-negative", ",", "and", "atypical", "bacteria", ".", "While", "small", "prospective", "studies", "have", "not", "revealed", "any", "significant", "drug-drug", "interaction", "between", "warfarin", "and", "levofloxacin", ",", "several", "case", "reports", "have", "indicated", "that", "levofloxacin", "may", "significantly", "potentiate", "the", "anticoagulation", "effect", "of", "warfarin", ".", "We", "report", "3", "cases", "of", "serious", "bleeding", "complications", "that", "appear", "to", "be", "the", "result", "of", "the", "interaction", "between", "warfarin", "and", "levofloxacin", ".", "Physicians", "should", "be", "aware", "of", "this", "potential", "interaction", "and", "use", "caution", "when", "prescribing", "levofloxacin", "to", "patients", "taking", "warfarin", "." ]
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19918264
FGFR4 Gly388Arg polymorphism and prostate cancer risk in Scottish men. Fibroblast growth factor receptor 4 (FGFR4), a member of the fibroblast growth receptor family, was recently reported to be more abundantly expressed in malignant than benign prostate cells. A single nucleotide polymorphism at position 388 of the FGFR4 amino-acid sequence results in the substitution of glycine (Gly) with arginine (Arg) and higher frequency of the ArgArg genotype was previously found in prostate cancer patients. DNA was extracted from the blood drawn from 399 prostate cancer patients, 150 BPH patients and 294 healthy community controls. Polymerase chain reaction was carried out and single nucleotide polymorphisms of FGFR4 were identified by restriction enzyme digestion. No overall association is detectable between the Arg allele and increased prostate cancer risk. Subgroup analysis shows a higher incidence of the heterozygous ArgGly genotype in cancer cases than in the combined group of BPH and controls (P<0.05); this difference is statistically significant between cancer and BPH patients but not between cancer cases and community controls. The single nucleotide polymorphism Gly(388)Arg in FGFR4 is not associated with increased risk of prostate cancer in Scottish men. This observation is in contrast with results from two previous studies conducted in the USA and Japan.
[ "FGFR4", "Gly388Arg", "polymorphism", "and", "prostate", "cancer", "risk", "in", "Scottish", "men", ".", "Fibroblast", "growth", "factor", "receptor", "4", "(", "FGFR4", ")", ",", "a", "member", "of", "the", "fibroblast", "growth", "receptor", "family", ",", "was", "recently", "reported", "to", "be", "more", "abundantly", "expressed", "in", "malignant", "than", "benign", "prostate", "cells", ".", "A", "single", "nucleotide", "polymorphism", "at", "position", "388", "of", "the", "FGFR4", "amino-acid", "sequence", "results", "in", "the", "substitution", "of", "glycine", "(", "Gly", ")", "with", "arginine", "(", "Arg", ")", "and", "higher", "frequency", "of", "the", "ArgArg", "genotype", "was", "previously", "found", "in", "prostate", "cancer", "patients", ".", "DNA", "was", "extracted", "from", "the", "blood", "drawn", "from", "399", "prostate", "cancer", "patients", ",", "150", "BPH", "patients", "and", "294", "healthy", "community", "controls", ".", "Polymerase", "chain", "reaction", "was", "carried", "out", "and", "single", "nucleotide", "polymorphisms", "of", "FGFR4", "were", "identified", "by", "restriction", "enzyme", "digestion", ".", "No", "overall", "association", "is", "detectable", "between", "the", "Arg", "allele", "and", "increased", "prostate", "cancer", "risk", ".", "Subgroup", "analysis", "shows", "a", "higher", "incidence", "of", "the", "heterozygous", "ArgGly", "genotype", "in", "cancer", "cases", "than", "in", "the", "combined", "group", "of", "BPH", "and", "controls", "(", "P", "<", "0.05", ")", ";", "this", "difference", "is", "statistically", "significant", "between", "cancer", "and", "BPH", "patients", "but", "not", "between", "cancer", "cases", "and", "community", "controls", ".", "The", "single", "nucleotide", "polymorphism", "Gly", "(", "388", ")", "Arg", "in", "FGFR4", "is", "not", "associated", "with", "increased", "risk", "of", "prostate", "cancer", "in", "Scottish", "men", ".", "This", "observation", "is", "in", "contrast", "with", "results", "from", "two", "previous", "studies", "conducted", "in", "the", "USA", "and", "Japan", "." ]
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20335448
A novel point mutation in helix 10 of the human glucocorticoid receptor causes generalized glucocorticoid resistance by disrupting the structure of the ligand-binding domain. CONTEXT: Generalized glucocorticoid resistance syndrome is a rare familial or sporadic condition characterized by partial insensitivity to glucocorticoids, caused by mutations in the glucocorticoid receptor (GR) gene. Most of the reported cases are adults, demonstrating symptoms associated with mineralocorticoid and/or adrenal androgen excess caused by compensatively increased secretion of the adrenocorticotropic hormone. PATIENT: We identified a new 2-yr-old female case of generalized glucocorticoid resistance syndrome. The patient (TJ) presented with a generalized seizure associated with hypoglycemia and hypokalemia. She also had hypertension and premature pubarche, whereas dexamethasone effectively suppressed these clinical manifestations. RESULTS: The patient's GR gene had a heterozygotic mutation (G-->A) at nucleotide position 2141 (exon 8), which resulted in substitution of arginine by glutamine at amino acid position 714 in the ligand-binding domain (LBD) of the GR alpha. Molecular analysis revealed that the mutant receptor had significantly impaired transactivation activity with a 2-fold reduction in affinity to ligand. It showed attenuated transactivation of the activation function (AF)-2 and reduced binding to a p160 nuclear receptor coactivator. Computer-based structural analysis revealed that replacement of arginine by glutamine at position 714 transmitted a conformational change to the LBD and the AF-2 transactivation surface, resulting in a decreased binding affinity to ligand and to the LXXLL coactivator motif. CONCLUSIONS: Dexamethasone treatment is effective in controlling the premature pubarche, hypoglycemia, hypertension, and hypokalemia in this child case, wherein arginine 714 plays a key role in the proper formation of the ligand-binding pocket and the AF-2 surface of the GR alpha LBD.
[ "A", "novel", "point", "mutation", "in", "helix", "10", "of", "the", "human", "glucocorticoid", "receptor", "causes", "generalized", "glucocorticoid", "resistance", "by", "disrupting", "the", "structure", "of", "the", "ligand-binding", "domain", ".", "CONTEXT", ":", "Generalized", "glucocorticoid", "resistance", "syndrome", "is", "a", "rare", "familial", "or", "sporadic", "condition", "characterized", "by", "partial", "insensitivity", "to", "glucocorticoids", ",", "caused", "by", "mutations", "in", "the", "glucocorticoid", "receptor", "(", "GR", ")", "gene", ".", "Most", "of", "the", "reported", "cases", "are", "adults", ",", "demonstrating", "symptoms", "associated", "with", "mineralocorticoid", "and/or", "adrenal", "androgen", "excess", "caused", "by", "compensatively", "increased", "secretion", "of", "the", "adrenocorticotropic", "hormone", ".", "PATIENT", ":", "We", "identified", "a", "new", "2-yr-old", "female", "case", "of", "generalized", "glucocorticoid", "resistance", "syndrome", ".", "The", "patient", "(", "TJ", ")", "presented", "with", "a", "generalized", "seizure", "associated", "with", "hypoglycemia", "and", "hypokalemia", ".", "She", "also", "had", "hypertension", "and", "premature", "pubarche", ",", "whereas", "dexamethasone", "effectively", "suppressed", "these", "clinical", "manifestations", ".", "RESULTS", ":", "The", "patient", "'s", "GR", "gene", "had", "a", "heterozygotic", "mutation", "(", "G", "--", ">", "A", ")", "at", "nucleotide", "position", "2141", "(", "exon", "8", ")", ",", "which", "resulted", "in", "substitution", "of", "arginine", "by", "glutamine", "at", "amino", "acid", "position", "714", "in", "the", "ligand-binding", "domain", "(", "LBD", ")", "of", "the", "GR", "alpha", ".", "Molecular", "analysis", "revealed", "that", "the", "mutant", "receptor", "had", "significantly", "impaired", "transactivation", "activity", "with", "a", "2-fold", "reduction", "in", "affinity", "to", "ligand", ".", "It", "showed", "attenuated", "transactivation", "of", "the", "activation", "function", "(", "AF", ")", "-2", "and", "reduced", "binding", "to", "a", "p160", "nuclear", "receptor", "coactivator", ".", "Computer-based", "structural", "analysis", "revealed", "that", "replacement", "of", "arginine", "by", "glutamine", "at", "position", "714", "transmitted", "a", "conformational", "change", "to", "the", "LBD", "and", "the", "AF-2", "transactivation", "surface", ",", "resulting", "in", "a", "decreased", "binding", "affinity", "to", "ligand", "and", "to", "the", "LXXLL", "coactivator", "motif", ".", "CONCLUSIONS", ":", "Dexamethasone", "treatment", "is", "effective", "in", "controlling", "the", "premature", "pubarche", ",", "hypoglycemia", ",", "hypertension", ",", "and", "hypokalemia", "in", "this", "child", "case", ",", "wherein", "arginine", "714", "plays", "a", "key", "role", "in", "the", "proper", "formation", "of", "the", "ligand-binding", "pocket", "and", "the", "AF-2", "surface", "of", "the", "GR", "alpha", "LBD", "." ]
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21695597
MHC region and risk of systemic lupus erythematosus in African American women. The major histocompatibility complex (MHC) on chromosome 6p21 is a key contributor to the genetic basis of systemic lupus erythematosus (SLE). Although SLE affects African Americans disproportionately compared to European Americans, there has been no comprehensive analysis of the MHC region in relationship to SLE in African Americans. We conducted a screening of the MHC region for 1,536 single nucleotide polymorphisms (SNPs) and the deletion of the C4A gene in a SLE case-control study (380 cases, 765 age-matched controls) nested within the prospective Black Women's Health Study. We also genotyped 1,509 ancestral informative markers throughout the genome to estimate European ancestry to control for population stratification due to population admixture. The most strongly associated SNP with SLE was the rs9271366 (odds ratio, OR = 1.70, p = 5.6 10(-5)) near the HLA-DRB1 gene. Conditional haplotype analysis revealed three other SNPs, rs204890 (OR = 1.86, p = 1.2 10(-4)), rs2071349 (OR = 1.53, p = 1.0 10(-3)), and rs2844580 (OR = 1.43, p = 1.3 10(-3)), to be associated with SLE independent of the rs9271366 SNP. In univariate analysis, the OR for the C4A deletion was 1.38, p = 0.075, but after simultaneous adjustment for the other four SNPs the odds ratio was 1.01, p = 0.98. A genotype score combining the four newly identified SNPs showed an additive risk according to the number of high-risk alleles (OR = 1.67 per high-risk allele, p < 0.0001). Our strongest signal, the rs9271366 SNP, was also associated with higher risk of SLE in a previous Chinese genome-wide association study (GWAS). In addition, two SNPs found in a GWAS of European ancestry women were confirmed in our study, indicating that African Americans share some genetic risk factors for SLE with European and Chinese subjects. In summary, we found four independent signals in the MHC region associated with risk of SLE in African American women.
[ "MHC", "region", "and", "risk", "of", "systemic", "lupus", "erythematosus", "in", "African", "American", "women", ".", "The", "major", "histocompatibility", "complex", "(", "MHC", ")", "on", "chromosome", "6p21", "is", "a", "key", "contributor", "to", "the", "genetic", "basis", "of", "systemic", "lupus", "erythematosus", "(", "SLE", ")", ".", "Although", "SLE", "affects", "African", "Americans", "disproportionately", "compared", "to", "European", "Americans", ",", "there", "has", "been", "no", "comprehensive", "analysis", "of", "the", "MHC", "region", "in", "relationship", "to", "SLE", "in", "African", "Americans", ".", "We", "conducted", "a", "screening", "of", "the", "MHC", "region", "for", "1,536", "single", "nucleotide", "polymorphisms", "(", "SNPs", ")", "and", "the", "deletion", "of", "the", "C4A", "gene", "in", "a", "SLE", "case-control", "study", "(", "380", "cases", ",", "765", "age-matched", "controls", ")", "nested", "within", "the", "prospective", "Black", "Women", "'s", "Health", "Study", ".", "We", "also", "genotyped", "1,509", "ancestral", "informative", "markers", "throughout", "the", "genome", "to", "estimate", "European", "ancestry", "to", "control", "for", "population", "stratification", "due", "to", "population", "admixture", ".", "The", "most", "strongly", "associated", "SNP", "with", "SLE", "was", "the", "rs9271366", "(", "odds", "ratio", ",", "OR", "=", "1.70", ",", "p", "=", "5.6", "10", "(", "-5", ")", ")", "near", "the", "HLA-DRB1", "gene", ".", "Conditional", "haplotype", "analysis", "revealed", "three", "other", "SNPs", ",", "rs204890", "(", "OR", "=", "1.86", ",", "p", "=", "1.2", "10", "(", "-4", ")", ")", ",", "rs2071349", "(", "OR", "=", "1.53", ",", "p", "=", "1.0", "10", "(", "-3", ")", ")", ",", "and", "rs2844580", "(", "OR", "=", "1.43", ",", "p", "=", "1.3", "10", "(", "-3", ")", ")", ",", "to", "be", "associated", "with", "SLE", "independent", "of", "the", "rs9271366", "SNP", ".", "In", "univariate", "analysis", ",", "the", "OR", "for", "the", "C4A", "deletion", "was", "1.38", ",", "p", "=", "0.075", ",", "but", "after", "simultaneous", "adjustment", "for", "the", "other", "four", "SNPs", "the", "odds", "ratio", "was", "1.01", ",", "p", "=", "0.98", ".", "A", "genotype", "score", "combining", "the", "four", "newly", "identified", "SNPs", "showed", "an", "additive", "risk", "according", "to", "the", "number", "of", "high-risk", "alleles", "(", "OR", "=", "1.67", "per", "high-risk", "allele", ",", "p", "<", "0.0001", ")", ".", "Our", "strongest", "signal", ",", "the", "rs9271366", "SNP", ",", "was", "also", "associated", "with", "higher", "risk", "of", "SLE", "in", "a", "previous", "Chinese", "genome-wide", "association", "study", "(", "GWAS", ")", ".", "In", "addition", ",", "two", "SNPs", "found", "in", "a", "GWAS", "of", "European", "ancestry", "women", "were", "confirmed", "in", "our", "study", ",", "indicating", "that", "African", "Americans", "share", "some", "genetic", "risk", "factors", "for", "SLE", "with", "European", "and", "Chinese", "subjects", ".", "In", "summary", ",", "we", "found", "four", "independent", "signals", "in", "the", "MHC", "region", "associated", "with", "risk", "of", "SLE", "in", "African", "American", "women", "." ]
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15191352
Severe form of thyroid hormone resistance in a patient with homozygous/hemizygous mutation of T3 receptor gene. Resistance to thyroid hormone syndrome (RTH) is a rare disorder, usually inherited as an autosomal dominant trait. Patients with RTH are usually euthyroid but can occasionally present with signs and symptoms of thyrotoxicosis or rarely with hypothyroidism. Affected individuals are usually heterozygous for mutations in the thyroid hormone receptor beta gene (TR-beta). We present a patient with RTH found to be homo-/hemizygous for a mutation in the TR-beta gene. The single nucleotide substitution I280S (1123T-->G) was present either on both alleles or in a hemizygous form with complete deletion of the second allele. The I280S mutation was recently reported in a heterozygous patient. The severe phenotype with seriously impaired intellectual development, hyperkinetic behaviour, tachycardia, hearing and visual impairment is probably due to the dominant negative effect of the I280S mutant protein and the absence of any functional TR-beta.
[ "Severe", "form", "of", "thyroid", "hormone", "resistance", "in", "a", "patient", "with", "homozygous/hemizygous", "mutation", "of", "T3", "receptor", "gene", ".", "Resistance", "to", "thyroid", "hormone", "syndrome", "(", "RTH", ")", "is", "a", "rare", "disorder", ",", "usually", "inherited", "as", "an", "autosomal", "dominant", "trait", ".", "Patients", "with", "RTH", "are", "usually", "euthyroid", "but", "can", "occasionally", "present", "with", "signs", "and", "symptoms", "of", "thyrotoxicosis", "or", "rarely", "with", "hypothyroidism", ".", "Affected", "individuals", "are", "usually", "heterozygous", "for", "mutations", "in", "the", "thyroid", "hormone", "receptor", "beta", "gene", "(", "TR-beta", ")", ".", "We", "present", "a", "patient", "with", "RTH", "found", "to", "be", "homo-/hemizygous", "for", "a", "mutation", "in", "the", "TR-beta", "gene", ".", "The", "single", "nucleotide", "substitution", "I280S", "(", "1123T", "--", ">", "G", ")", "was", "present", "either", "on", "both", "alleles", "or", "in", "a", "hemizygous", "form", "with", "complete", "deletion", "of", "the", "second", "allele", ".", "The", "I280S", "mutation", "was", "recently", "reported", "in", "a", "heterozygous", "patient", ".", "The", "severe", "phenotype", "with", "seriously", "impaired", "intellectual", "development", ",", "hyperkinetic", "behaviour", ",", "tachycardia", ",", "hearing", "and", "visual", "impairment", "is", "probably", "due", "to", "the", "dominant", "negative", "effect", "of", "the", "I280S", "mutant", "protein", "and", "the", "absence", "of", "any", "functional", "TR-beta", "." ]
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15814629
The number of lymph node metastases in gastric cancer correlates with the angiotensin I-converting enzyme gene insertion/deletion polymorphism. PURPOSE: In the present study, we aimed to substantiate the putative significance of angiotensin I-converting enzyme (ACE) on gastric cancer biology by investigating the influence of its gene polymorphism on gastric cancer progression. EXPERIMENTAL DESIGN: Genomic DNA was purified from peripheral blood mononuclear cells or tissue specimens. Amplified ACE gene fragments were separated on agarose gels. D or I alleles were identified by the presence of 190- or 490-bp fragments, respectively. Local expression of ACE was investigated by immunohistochemistry. RESULTS: Twenty-four of 113 (21%) gastric cancer patients had the II, 57 (51%) the ID, and 32 (28%) the DD genotype. The distribution of the ACE genotypes did not differ significantly from the control group of 189 patients without gastric cancer. However, the ACE genotypes correlated with the number of lymph node metastases and the Unio Internationale Contra Cancrum (UICC) tumor stage. Patients with the II genotype had a highly significantly smaller number of lymph node metastases (P < 0.001) and a significantly lower UICC tumor stage (P = 0.01) than patients with the DD genotype. No correlation was found between tumor type, tumor location, local tumor growth, distant metastases, and the ACE genotype. The expression of ACE in gastric cancer was investigated by immunohistochemistry in 100 of 113 patients. ACE was expressed by endothelial cells in all (100%) specimens and by tumor cells in 56 (56%) specimens. CONCLUSIONS: Our study shows that ACE is expressed locally in gastric cancer and that the gene polymorphism influences metastatic behavior.
[ "The", "number", "of", "lymph", "node", "metastases", "in", "gastric", "cancer", "correlates", "with", "the", "angiotensin", "I-converting", "enzyme", "gene", "insertion/deletion", "polymorphism", ".", "PURPOSE", ":", "In", "the", "present", "study", ",", "we", "aimed", "to", "substantiate", "the", "putative", "significance", "of", "angiotensin", "I-converting", "enzyme", "(", "ACE", ")", "on", "gastric", "cancer", "biology", "by", "investigating", "the", "influence", "of", "its", "gene", "polymorphism", "on", "gastric", "cancer", "progression", ".", "EXPERIMENTAL", "DESIGN", ":", "Genomic", "DNA", "was", "purified", "from", "peripheral", "blood", "mononuclear", "cells", "or", "tissue", "specimens", ".", "Amplified", "ACE", "gene", "fragments", "were", "separated", "on", "agarose", "gels", ".", "D", "or", "I", "alleles", "were", "identified", "by", "the", "presence", "of", "190-", "or", "490-bp", "fragments", ",", "respectively", ".", "Local", "expression", "of", "ACE", "was", "investigated", "by", "immunohistochemistry", ".", "RESULTS", ":", "Twenty-four", "of", "113", "(", "21", "%", ")", "gastric", "cancer", "patients", "had", "the", "II", ",", "57", "(", "51", "%", ")", "the", "ID", ",", "and", "32", "(", "28", "%", ")", "the", "DD", "genotype", ".", "The", "distribution", "of", "the", "ACE", "genotypes", "did", "not", "differ", "significantly", "from", "the", "control", "group", "of", "189", "patients", "without", "gastric", "cancer", ".", "However", ",", "the", "ACE", "genotypes", "correlated", "with", "the", "number", "of", "lymph", "node", "metastases", "and", "the", "Unio", "Internationale", "Contra", "Cancrum", "(", "UICC", ")", "tumor", "stage", ".", "Patients", "with", "the", "II", "genotype", "had", "a", "highly", "significantly", "smaller", "number", "of", "lymph", "node", "metastases", "(", "P", "<", "0.001", ")", "and", "a", "significantly", "lower", "UICC", "tumor", "stage", "(", "P", "=", "0.01", ")", "than", "patients", "with", "the", "DD", "genotype", ".", "No", "correlation", "was", "found", "between", "tumor", "type", ",", "tumor", "location", ",", "local", "tumor", "growth", ",", "distant", "metastases", ",", "and", "the", "ACE", "genotype", ".", "The", "expression", "of", "ACE", "in", "gastric", "cancer", "was", "investigated", "by", "immunohistochemistry", "in", "100", "of", "113", "patients", ".", "ACE", "was", "expressed", "by", "endothelial", "cells", "in", "all", "(", "100", "%", ")", "specimens", "and", "by", "tumor", "cells", "in", "56", "(", "56", "%", ")", "specimens", ".", "CONCLUSIONS", ":", "Our", "study", "shows", "that", "ACE", "is", "expressed", "locally", "in", "gastric", "cancer", "and", "that", "the", "gene", "polymorphism", "influences", "metastatic", "behavior", "." ]
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16541406
Distinct patterns of germ-line deletions in MLH1 and MSH2: the implication of Alu repetitive element in the genetic etiology of Lynch syndrome (HNPCC). A relatively high frequency of germ-line genomic rearrangements in MLH1 and MSH2 has been reported among Lynch Syndrome (HNPCC) patients from different ethnic populations. To investigate the underlying molecular mechanisms, we characterized the DNA breakpoints of 11 germ-line deletions, six for MLH1 and five for MSH2. Distinct deletion patterns were found for the two genes. The five cases of MSH2 deletions result exclusively from intragenic unequal recombination mediated by repetitive Alu sequences. In contrast, five out of the six MLH1 deletions are due to recombinations involving sequences of no significant homology (P=0.015). A detailed analysis of the DNA breakpoints in the two genes, previously characterized by other groups, validated the observation that Alu-mediated unequal recombination is the main type of deletion in MSH2 (n=34), but not in MLH1 (n=21) (P<0.0001). Plotting the distribution of known DNA breakpoints among the introns of the two genes showed that, the highest breakpoint density is co-localized with the highest Alu density. Our study suggests that Alu is a promoting factor for the genomic recombinations in both MLH1 and MSH2, and the local Alu density may be involved in shaping the deletion pattern.
[ "Distinct", "patterns", "of", "germ-line", "deletions", "in", "MLH1", "and", "MSH2", ":", "the", "implication", "of", "Alu", "repetitive", "element", "in", "the", "genetic", "etiology", "of", "Lynch", "syndrome", "(", "HNPCC", ")", ".", "A", "relatively", "high", "frequency", "of", "germ-line", "genomic", "rearrangements", "in", "MLH1", "and", "MSH2", "has", "been", "reported", "among", "Lynch", "Syndrome", "(", "HNPCC", ")", "patients", "from", "different", "ethnic", "populations", ".", "To", "investigate", "the", "underlying", "molecular", "mechanisms", ",", "we", "characterized", "the", "DNA", "breakpoints", "of", "11", "germ-line", "deletions", ",", "six", "for", "MLH1", "and", "five", "for", "MSH2", ".", "Distinct", "deletion", "patterns", "were", "found", "for", "the", "two", "genes", ".", "The", "five", "cases", "of", "MSH2", "deletions", "result", "exclusively", "from", "intragenic", "unequal", "recombination", "mediated", "by", "repetitive", "Alu", "sequences", ".", "In", "contrast", ",", "five", "out", "of", "the", "six", "MLH1", "deletions", "are", "due", "to", "recombinations", "involving", "sequences", "of", "no", "significant", "homology", "(", "P=0.015", ")", ".", "A", "detailed", "analysis", "of", "the", "DNA", "breakpoints", "in", "the", "two", "genes", ",", "previously", "characterized", "by", "other", "groups", ",", "validated", "the", "observation", "that", "Alu-mediated", "unequal", "recombination", "is", "the", "main", "type", "of", "deletion", "in", "MSH2", "(", "n=34", ")", ",", "but", "not", "in", "MLH1", "(", "n=21", ")", "(", "P", "<", "0.0001", ")", ".", "Plotting", "the", "distribution", "of", "known", "DNA", "breakpoints", "among", "the", "introns", "of", "the", "two", "genes", "showed", "that", ",", "the", "highest", "breakpoint", "density", "is", "co-localized", "with", "the", "highest", "Alu", "density", ".", "Our", "study", "suggests", "that", "Alu", "is", "a", "promoting", "factor", "for", "the", "genomic", "recombinations", "in", "both", "MLH1", "and", "MSH2", ",", "and", "the", "local", "Alu", "density", "may", "be", "involved", "in", "shaping", "the", "deletion", "pattern", "." ]
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20583543
Molecular diagnosis of 46,XY DSD and identification of a novel 8 nucleotide deletion in exon 1 of the SRD5A2 gene. Phenotypic presentation of 46,XY DSD depends on the underlying defects. Defect in androgen action on the target tissues or production of active metabolite share common morphological features. Molecular study may help differentiating these abnormalities with precision. Mutational analysis of androgen receptor (AR) and SRD5A2 genes was performed in 29 patients with 46,XY DSD, by PCR-SSCP. The amplicons that showed an aberrant migration in SSCP were subjected to sequencing. Interestingly, six patients from 4 unrelated families (a pair of sibs, uncle/nephew and other two isolated) were identified with mutations in SRD5A2 gene. In five patients p.R246Q missense mutation was detected, of which four were homozygous and one was compound heterozygous: g.80_87delT CGCGAAG (p.A27fsX132) and p.R246Q. Another patient with isolated micropenis harbored a heterozygous p.G196S missense mutation. No AR gene mutation was detected. In conclusion, our study suggests that p.R246Q mutation is common amongst patients with SRD5A2 gene defect from the Northern states of India. Also, it records a novel deletion in exon 1 of SRD5A2 gene in a patient with severe hypospadias.
[ "Molecular", "diagnosis", "of", "46", ",", "XY", "DSD", "and", "identification", "of", "a", "novel", "8", "nucleotide", "deletion", "in", "exon", "1", "of", "the", "SRD5A2", "gene", ".", "Phenotypic", "presentation", "of", "46", ",", "XY", "DSD", "depends", "on", "the", "underlying", "defects", ".", "Defect", "in", "androgen", "action", "on", "the", "target", "tissues", "or", "production", "of", "active", "metabolite", "share", "common", "morphological", "features", ".", "Molecular", "study", "may", "help", "differentiating", "these", "abnormalities", "with", "precision", ".", "Mutational", "analysis", "of", "androgen", "receptor", "(", "AR", ")", "and", "SRD5A2", "genes", "was", "performed", "in", "29", "patients", "with", "46", ",", "XY", "DSD", ",", "by", "PCR-SSCP", ".", "The", "amplicons", "that", "showed", "an", "aberrant", "migration", "in", "SSCP", "were", "subjected", "to", "sequencing", ".", "Interestingly", ",", "six", "patients", "from", "4", "unrelated", "families", "(", "a", "pair", "of", "sibs", ",", "uncle/nephew", "and", "other", "two", "isolated", ")", "were", "identified", "with", "mutations", "in", "SRD5A2", "gene", ".", "In", "five", "patients", "p.R246Q", "missense", "mutation", "was", "detected", ",", "of", "which", "four", "were", "homozygous", "and", "one", "was", "compound", "heterozygous", ":", "g.80_87delT", "CGCGAAG", "(", "p.A27fsX132", ")", "and", "p.R246Q", ".", "Another", "patient", "with", "isolated", "micropenis", "harbored", "a", "heterozygous", "p.G196S", "missense", "mutation", ".", "No", "AR", "gene", "mutation", "was", "detected", ".", "In", "conclusion", ",", "our", "study", "suggests", "that", "p.R246Q", "mutation", "is", "common", "amongst", "patients", "with", "SRD5A2", "gene", "defect", "from", "the", "Northern", "states", "of", "India", ".", "Also", ",", "it", "records", "a", "novel", "deletion", "in", "exon", "1", "of", "SRD5A2", "gene", "in", "a", "patient", "with", "severe", "hypospadias", "." ]
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20722491
Safety of capecitabine: a review. IMPORTANCE OF THE FIELD: Fluoropyrimidines, in particular 5-fluorouracil (5-FU), have been the mainstay of treatment for several solid tumors, including colorectal, breast and head and neck cancers, for > 40 years. AREAS COVERED IN THIS REVIEW: This article reviews the pharmacology and efficacy of capecitabine with a special emphasis on its safety. WHAT THE READER WILL GAIN: The reader will gain better insight into the safety of capecitabine in special populations such as patients with advanced age, renal and kidney disease. We also explore different dosing and schedules of capecitabine administration. TAKE HOME MESSAGE: Capecitabine is an oral prodrug of 5-FU and was developed to fulfill the need for a more convenient therapy and provide an improved safety/efficacy profile. It has shown promising results alone or in combination with other chemotherapeutic agents in colorectal, breast, pancreaticobiliary, gastric, renal cell and head and neck cancers. The most commonly reported toxic effects of capecitabine are diarrhea, nausea, vomiting, stomatitis and hand-foot syndrome. Capecitabine has a well-established safety profile and can be given safely to patients with advanced age, hepatic and renal dysfunctions.
[ "Safety", "of", "capecitabine", ":", "a", "review", ".", "IMPORTANCE", "OF", "THE", "FIELD", ":", "Fluoropyrimidines", ",", "in", "particular", "5-fluorouracil", "(", "5-FU", ")", ",", "have", "been", "the", "mainstay", "of", "treatment", "for", "several", "solid", "tumors", ",", "including", "colorectal", ",", "breast", "and", "head", "and", "neck", "cancers", ",", "for", ">", "40", "years", ".", "AREAS", "COVERED", "IN", "THIS", "REVIEW", ":", "This", "article", "reviews", "the", "pharmacology", "and", "efficacy", "of", "capecitabine", "with", "a", "special", "emphasis", "on", "its", "safety", ".", "WHAT", "THE", "READER", "WILL", "GAIN", ":", "The", "reader", "will", "gain", "better", "insight", "into", "the", "safety", "of", "capecitabine", "in", "special", "populations", "such", "as", "patients", "with", "advanced", "age", ",", "renal", "and", "kidney", "disease", ".", "We", "also", "explore", "different", "dosing", "and", "schedules", "of", "capecitabine", "administration", ".", "TAKE", "HOME", "MESSAGE", ":", "Capecitabine", "is", "an", "oral", "prodrug", "of", "5-FU", "and", "was", "developed", "to", "fulfill", "the", "need", "for", "a", "more", "convenient", "therapy", "and", "provide", "an", "improved", "safety/efficacy", "profile", ".", "It", "has", "shown", "promising", "results", "alone", "or", "in", "combination", "with", "other", "chemotherapeutic", "agents", "in", "colorectal", ",", "breast", ",", "pancreaticobiliary", ",", "gastric", ",", "renal", "cell", "and", "head", "and", "neck", "cancers", ".", "The", "most", "commonly", "reported", "toxic", "effects", "of", "capecitabine", "are", "diarrhea", ",", "nausea", ",", "vomiting", ",", "stomatitis", "and", "hand-foot", "syndrome", ".", "Capecitabine", "has", "a", "well-established", "safety", "profile", "and", "can", "be", "given", "safely", "to", "patients", "with", "advanced", "age", ",", "hepatic", "and", "renal", "dysfunctions", "." ]
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15523499
Haplotype structure of the beta adrenergic receptor genes in US Caucasians and African Americans. The beta-adrenergic receptors (beta-AR) are G protein-coupled receptors activated by epinephrine and norepinephrine and are involved in a variety of their physiological functions. Previously, three beta-AR genes (ADRB1, ADRB2 and ADRB3) were resequenced, identifying polymorphisms that were used in genetic association studies of cardiovascular and metabolic disorders. These studies have produced intriguing but inconsistent results, potentially because the known functional variants: ADRB1 Arg389Gly and Gly49Ser, ADRB2 Arg16Gly and Gln27Glu, and ADRB3 Arg64Trp provided an incomplete picture of the total functional diversity at these genes. Therefore, we created marker panels for each beta-AR gene that included the known functional markers and also other markers evenly spaced and with sufficient density to identify haplotype block structure and to maximize haplotype diversity. A total of 27 markers were genotyped in 96 US Caucasians and 96 African Americans. In both populations and for each gene, a single block with little evidence of historical recombination was observed. For each gene, haplotype captured most of the information content of each functional locus, even if that locus was not genotyped, and presumably haplotype would capture the signal from unknown functional loci whose alleles are of moderate abundance. This study demonstrates the utility of using beta-AR gene haplotype maps and marker panels as tools for linkage studies on beta-AR function.
[ "Haplotype", "structure", "of", "the", "beta", "adrenergic", "receptor", "genes", "in", "US", "Caucasians", "and", "African", "Americans", ".", "The", "beta-adrenergic", "receptors", "(", "beta-AR", ")", "are", "G", "protein-coupled", "receptors", "activated", "by", "epinephrine", "and", "norepinephrine", "and", "are", "involved", "in", "a", "variety", "of", "their", "physiological", "functions", ".", "Previously", ",", "three", "beta-AR", "genes", "(", "ADRB1", ",", "ADRB2", "and", "ADRB3", ")", "were", "resequenced", ",", "identifying", "polymorphisms", "that", "were", "used", "in", "genetic", "association", "studies", "of", "cardiovascular", "and", "metabolic", "disorders", ".", "These", "studies", "have", "produced", "intriguing", "but", "inconsistent", "results", ",", "potentially", "because", "the", "known", "functional", "variants", ":", "ADRB1", "Arg389Gly", "and", "Gly49Ser", ",", "ADRB2", "Arg16Gly", "and", "Gln27Glu", ",", "and", "ADRB3", "Arg64Trp", "provided", "an", "incomplete", "picture", "of", "the", "total", "functional", "diversity", "at", "these", "genes", ".", "Therefore", ",", "we", "created", "marker", "panels", "for", "each", "beta-AR", "gene", "that", "included", "the", "known", "functional", "markers", "and", "also", "other", "markers", "evenly", "spaced", "and", "with", "sufficient", "density", "to", "identify", "haplotype", "block", "structure", "and", "to", "maximize", "haplotype", "diversity", ".", "A", "total", "of", "27", "markers", "were", "genotyped", "in", "96", "US", "Caucasians", "and", "96", "African", "Americans", ".", "In", "both", "populations", "and", "for", "each", "gene", ",", "a", "single", "block", "with", "little", "evidence", "of", "historical", "recombination", "was", "observed", ".", "For", "each", "gene", ",", "haplotype", "captured", "most", "of", "the", "information", "content", "of", "each", "functional", "locus", ",", "even", "if", "that", "locus", "was", "not", "genotyped", ",", "and", "presumably", "haplotype", "would", "capture", "the", "signal", "from", "unknown", "functional", "loci", "whose", "alleles", "are", "of", "moderate", "abundance", ".", "This", "study", "demonstrates", "the", "utility", "of", "using", "beta-AR", "gene", "haplotype", "maps", "and", "marker", "panels", "as", "tools", "for", "linkage", "studies", "on", "beta-AR", "function", "." ]
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16737910
Identification of the nuclear localization motif in the ETV6 (TEL) protein. ETV6, or Translocation-Ets-Leukemia (TEL), is an ETS family transcriptional repressor that is essential for establishing hematopoiesis in neonatal bone marrow, and is frequently a target of chromosomal translocations in human cancer. ETV6 is predominantly a nuclear phosphoprotein that represses transcription by binding directly to the promoters of target genes. The nuclear localization mechanism of ETV6, however, is not well understood. In this report, we provide evidence that a nuclear localization signal (NLS) exists in the C-terminal region of ETV6. ETV6 proteins with mutations outside of amino acids 332-452 localize to the nucleus, whereas proteins with mutations within amino acids 332-452 remain in the cytoplasm. Furthermore, when a fragment of ETV6 comprised of amino acids 332-452 was fused to cytoplasmic beta-galactosidase protein, the fusion protein was able to enter the nucleus. These results strongly indicate that residues 332-452 mediate nuclear localization of ETV6.
[ "Identification", "of", "the", "nuclear", "localization", "motif", "in", "the", "ETV6", "(", "TEL", ")", "protein", ".", "ETV6", ",", "or", "Translocation-Ets-Leukemia", "(", "TEL", ")", ",", "is", "an", "ETS", "family", "transcriptional", "repressor", "that", "is", "essential", "for", "establishing", "hematopoiesis", "in", "neonatal", "bone", "marrow", ",", "and", "is", "frequently", "a", "target", "of", "chromosomal", "translocations", "in", "human", "cancer", ".", "ETV6", "is", "predominantly", "a", "nuclear", "phosphoprotein", "that", "represses", "transcription", "by", "binding", "directly", "to", "the", "promoters", "of", "target", "genes", ".", "The", "nuclear", "localization", "mechanism", "of", "ETV6", ",", "however", ",", "is", "not", "well", "understood", ".", "In", "this", "report", ",", "we", "provide", "evidence", "that", "a", "nuclear", "localization", "signal", "(", "NLS", ")", "exists", "in", "the", "C-terminal", "region", "of", "ETV6", ".", "ETV6", "proteins", "with", "mutations", "outside", "of", "amino", "acids", "332-452", "localize", "to", "the", "nucleus", ",", "whereas", "proteins", "with", "mutations", "within", "amino", "acids", "332-452", "remain", "in", "the", "cytoplasm", ".", "Furthermore", ",", "when", "a", "fragment", "of", "ETV6", "comprised", "of", "amino", "acids", "332-452", "was", "fused", "to", "cytoplasmic", "beta-galactosidase", "protein", ",", "the", "fusion", "protein", "was", "able", "to", "enter", "the", "nucleus", ".", "These", "results", "strongly", "indicate", "that", "residues", "332-452", "mediate", "nuclear", "localization", "of", "ETV6", "." ]
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16822828
Genotyping of five chinese patients with 17alpha-hydroxylase deficiency diagnosed through high-performance liquid chromatography serum adrenal profile: identification of two novel CYP17 mutations. CONTEXT: 17alpha-Hydroxylase deficiency is a rare form of congenital adrenal hyperplasia caused by CYP17 gene mutations. OBJECTIVE: Five Chinese patients with 17alpha-hydroxylase deficiency were genotyped. PATIENTS: The five patients derived from four families living in Shandong Province, China. The diagnosis of 17alpha-hydroxylase deficiency was initially established through HPLC serum adrenal profiles in Qilu Hospital, China, from 1983-1993. RESULTS: Three CYP17 gene mutations were identified from these patients. Among them, V311fs and Y329fs are two novel frame-shifting mutations. V311fs is an 8-bp nucleotide (TTAAATGG) deletion in exon 5. Y329fs is a deletion-insertion combined mutation (TAC-->AA) at codon 329 in exon 6. Two homozygotes for Y329fs and one compound heterozygote for Y329fs and V311fs were identified from three different families. Two homozygous sisters for the D487_S488_F489 deletion were identified. CONCLUSION: The results confirmed the diagnostic value of the HPLC serum adrenal profile for 17alpha-hydroxylase deficiency. The D487_S488_F489 deletion had been identified in two previously genotyped Chinese families. In our present study, a third Chinese family with this mutation was identified, suggesting that this mutation is a prevalent CYP17 mutation in the Chinese population. The identification of Y329fs mutation in addition to three previously identified mutations at codon 329 suggests that codon 329 is an unstable point of the CYP17 gene. The mutations identified from our five patients appear to be random, but the recurrence of the Y329fs mutation may be attributed to a founder effect. Our studies suggest that 17alpha-hydroxylase deficiency may not be rare in the Chinese population.
[ "Genotyping", "of", "five", "chinese", "patients", "with", "17alpha-hydroxylase", "deficiency", "diagnosed", "through", "high-performance", "liquid", "chromatography", "serum", "adrenal", "profile", ":", "identification", "of", "two", "novel", "CYP17", "mutations", ".", "CONTEXT", ":", "17alpha-Hydroxylase", "deficiency", "is", "a", "rare", "form", "of", "congenital", "adrenal", "hyperplasia", "caused", "by", "CYP17", "gene", "mutations", ".", "OBJECTIVE", ":", "Five", "Chinese", "patients", "with", "17alpha-hydroxylase", "deficiency", "were", "genotyped", ".", "PATIENTS", ":", "The", "five", "patients", "derived", "from", "four", "families", "living", "in", "Shandong", "Province", ",", "China", ".", "The", "diagnosis", "of", "17alpha-hydroxylase", "deficiency", "was", "initially", "established", "through", "HPLC", "serum", "adrenal", "profiles", "in", "Qilu", "Hospital", ",", "China", ",", "from", "1983-1993", ".", "RESULTS", ":", "Three", "CYP17", "gene", "mutations", "were", "identified", "from", "these", "patients", ".", "Among", "them", ",", "V311fs", "and", "Y329fs", "are", "two", "novel", "frame-shifting", "mutations", ".", "V311fs", "is", "an", "8-bp", "nucleotide", "(", "TTAAATGG", ")", "deletion", "in", "exon", "5", ".", "Y329fs", "is", "a", "deletion-insertion", "combined", "mutation", "(", "TAC", "--", ">", "AA", ")", "at", "codon", "329", "in", "exon", "6", ".", "Two", "homozygotes", "for", "Y329fs", "and", "one", "compound", "heterozygote", "for", "Y329fs", "and", "V311fs", "were", "identified", "from", "three", "different", "families", ".", "Two", "homozygous", "sisters", "for", "the", "D487_S488_F489", "deletion", "were", "identified", ".", "CONCLUSION", ":", "The", "results", "confirmed", "the", "diagnostic", "value", "of", "the", "HPLC", "serum", "adrenal", "profile", "for", "17alpha-hydroxylase", "deficiency", ".", "The", "D487_S488_F489", "deletion", "had", "been", "identified", "in", "two", "previously", "genotyped", "Chinese", "families", ".", "In", "our", "present", "study", ",", "a", "third", "Chinese", "family", "with", "this", "mutation", "was", "identified", ",", "suggesting", "that", "this", "mutation", "is", "a", "prevalent", "CYP17", "mutation", "in", "the", "Chinese", "population", ".", "The", "identification", "of", "Y329fs", "mutation", "in", "addition", "to", "three", "previously", "identified", "mutations", "at", "codon", "329", "suggests", "that", "codon", "329", "is", "an", "unstable", "point", "of", "the", "CYP17", "gene", ".", "The", "mutations", "identified", "from", "our", "five", "patients", "appear", "to", "be", "random", ",", "but", "the", "recurrence", "of", "the", "Y329fs", "mutation", "may", "be", "attributed", "to", "a", "founder", "effect", ".", "Our", "studies", "suggest", "that", "17alpha-hydroxylase", "deficiency", "may", "not", "be", "rare", "in", "the", "Chinese", "population", "." ]
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17351238
A dramatic drop in blood pressure following prehospital GTN administration. A male in his sixties with no history of cardiac chest pain awoke with chest pain following an afternoon sleep. The patient did not self medicate. The patient's observations were within normal limits, he was administered oxygen via a face mask and glyceryl trinitrate (GTN). Several minutes after the GTN the patient experienced a sudden drop in blood pressure and heart rate, this was rectified by atropine sulphate and a fluid challenge. There was no further deterioration in the patient's condition during transport to hospital. There are very few documented case like this in the prehospital scientific literature. The cause appears to be the Bezold-Jarish reflex, stimulation of the ventricular walls which in turn decreases sympathetic outflow from the vasomotor centre. Prehospital care providers who are managing any patient with a syncopal episode that fails to recover within a reasonable time frame should consider the Bezold-Jarisch reflex as the cause and manage the patient accordingly.
[ "A", "dramatic", "drop", "in", "blood", "pressure", "following", "prehospital", "GTN", "administration", ".", "A", "male", "in", "his", "sixties", "with", "no", "history", "of", "cardiac", "chest", "pain", "awoke", "with", "chest", "pain", "following", "an", "afternoon", "sleep", ".", "The", "patient", "did", "not", "self", "medicate", ".", "The", "patient", "'s", "observations", "were", "within", "normal", "limits", ",", "he", "was", "administered", "oxygen", "via", "a", "face", "mask", "and", "glyceryl", "trinitrate", "(", "GTN", ")", ".", "Several", "minutes", "after", "the", "GTN", "the", "patient", "experienced", "a", "sudden", "drop", "in", "blood", "pressure", "and", "heart", "rate", ",", "this", "was", "rectified", "by", "atropine", "sulphate", "and", "a", "fluid", "challenge", ".", "There", "was", "no", "further", "deterioration", "in", "the", "patient", "'s", "condition", "during", "transport", "to", "hospital", ".", "There", "are", "very", "few", "documented", "case", "like", "this", "in", "the", "prehospital", "scientific", "literature", ".", "The", "cause", "appears", "to", "be", "the", "Bezold-Jarish", "reflex", ",", "stimulation", "of", "the", "ventricular", "walls", "which", "in", "turn", "decreases", "sympathetic", "outflow", "from", "the", "vasomotor", "centre", ".", "Prehospital", "care", "providers", "who", "are", "managing", "any", "patient", "with", "a", "syncopal", "episode", "that", "fails", "to", "recover", "within", "a", "reasonable", "time", "frame", "should", "consider", "the", "Bezold-Jarisch", "reflex", "as", "the", "cause", "and", "manage", "the", "patient", "accordingly", "." ]
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18791947
A case of Bernard-Soulier Syndrome due to a homozygous four bases deletion (TGAG) of GPIbalpha gene: lack of GPIbalpha but absence of bleeding. More than 20 DNA mutations with different inheritance pattern have been described in patients with Bernard-Soulier Syndrome (BSS), leading to abnormal or absent synthesis and/or expression of GPIbalpha. Clinical phenotype shows considerable variation between individuals, such as bleeding, platelet count and the percentage of large platelets. We describe in a BSS patient the first case of homozygous four bases deletion (TGAG) in the gpIbalpha gene coding sequence, leading to a premature stop codon. In the propositus, blood smears revealed giant platelets (30 x 10(9) platelets/L), and platelet agglutination to ristocetin was absent. Propositus' parents are consanguineous. His father and paternal grandmother showed a mild thrombocytopenia (108 x 10(9)/L and 120 x 10(9)/L platelets respectively) while mothers and sister's referred normal platelet counts. The surface expression of GPIbalpha was practically undetectable by flow-cytometry and western blot in the patient and was reduced in the father. Proband's DNA analysis revealed a homozygous four-base-pair deletion (TGAG), starting from the last base of the codon for Ser39, leading to a coding frame shift with a new termination codon after 11 novel amino acids. The same mutation was seen in heterozygosis in both parents. This is the first report of GPIbalpha TGAG deletion in homozygous state even if the defect has already been described in a case of compound heterozygosis. Surprisingly, the propositus does not report any spontaneous bleeding tendency.
[ "A", "case", "of", "Bernard-Soulier", "Syndrome", "due", "to", "a", "homozygous", "four", "bases", "deletion", "(", "TGAG", ")", "of", "GPIbalpha", "gene", ":", "lack", "of", "GPIbalpha", "but", "absence", "of", "bleeding", ".", "More", "than", "20", "DNA", "mutations", "with", "different", "inheritance", "pattern", "have", "been", "described", "in", "patients", "with", "Bernard-Soulier", "Syndrome", "(", "BSS", ")", ",", "leading", "to", "abnormal", "or", "absent", "synthesis", "and/or", "expression", "of", "GPIbalpha", ".", "Clinical", "phenotype", "shows", "considerable", "variation", "between", "individuals", ",", "such", "as", "bleeding", ",", "platelet", "count", "and", "the", "percentage", "of", "large", "platelets", ".", "We", "describe", "in", "a", "BSS", "patient", "the", "first", "case", "of", "homozygous", "four", "bases", "deletion", "(", "TGAG", ")", "in", "the", "gpIbalpha", "gene", "coding", "sequence", ",", "leading", "to", "a", "premature", "stop", "codon", ".", "In", "the", "propositus", ",", "blood", "smears", "revealed", "giant", "platelets", "(", "30", "x", "10", "(", "9", ")", "platelets/L", ")", ",", "and", "platelet", "agglutination", "to", "ristocetin", "was", "absent", ".", "Propositus", "'", "parents", "are", "consanguineous", ".", "His", "father", "and", "paternal", "grandmother", "showed", "a", "mild", "thrombocytopenia", "(", "108", "x", "10", "(", "9", ")", "/L", "and", "120", "x", "10", "(", "9", ")", "/L", "platelets", "respectively", ")", "while", "mothers", "and", "sister", "'s", "referred", "normal", "platelet", "counts", ".", "The", "surface", "expression", "of", "GPIbalpha", "was", "practically", "undetectable", "by", "flow-cytometry", "and", "western", "blot", "in", "the", "patient", "and", "was", "reduced", "in", "the", "father", ".", "Proband", "'s", "DNA", "analysis", "revealed", "a", "homozygous", "four-base-pair", "deletion", "(", "TGAG", ")", ",", "starting", "from", "the", "last", "base", "of", "the", "codon", "for", "Ser39", ",", "leading", "to", "a", "coding", "frame", "shift", "with", "a", "new", "termination", "codon", "after", "11", "novel", "amino", "acids", ".", "The", "same", "mutation", "was", "seen", "in", "heterozygosis", "in", "both", "parents", ".", "This", "is", "the", "first", "report", "of", "GPIbalpha", "TGAG", "deletion", "in", "homozygous", "state", "even", "if", "the", "defect", "has", "already", "been", "described", "in", "a", "case", "of", "compound", "heterozygosis", ".", "Surprisingly", ",", "the", "propositus", "does", "not", "report", "any", "spontaneous", "bleeding", "tendency", "." ]
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19370764
Identification and molecular characterization of six novel mutations in the UDP-N-acetylglucosamine-1-phosphotransferase gamma subunit (GNPTG) gene in patients with mucolipidosis III gamma. Mucolipidosis type III (MLIII) is an autosomal recessive disorder affecting lysosomal hydrolase trafficking. In a study of 10 patients from seven families with a clinical phenotype and enzymatic diagnosis of MLIII, six novel GNPTG gene mutations were identified. These included missense (p.T286M) and nonsense (p.W111X) mutations and a transition in the obligate AG-dinucleotide of the intron 8 acceptor splice site (c.610-2A>G). Three microdeletions were also identified, two of which (c.611delG and c.640_667del28) were located within the coding region whereas one (c.609+28_610-16del) was located entirely within intron 8. RT-PCR analysis of the c.610-2A>G transition demonstrated that the change altered splicing, leading to the production of two distinct aberrantly spliced forms, viz. the skipping of exon 9 (p.G204_K247del) or the retention of introns 8 and 9 (p.G204VfsX28). RT-PCR analysis, performed on a patient homozygous for the intronic deletion (c.609+28_610-16del), failed to detect any GNPTG RNA transcripts. To determine whether c.609+28_610-16del allele-derived transcripts were subject to nonsense-mediated mRNA decay (NMD), patient fibroblasts were incubated with the protein synthesis inhibitor anisomycin. An RT-PCR fragment retaining 43 bp of intron 8 was consistently detected suggesting that the 33-bp genomic deletion had elicited NMD. Quantitative real-time PCR and GNPTG western blot analysis confirmed that the homozygous microdeletion p.G204VfsX17 had elicited NMD resulting in failure to synthesize GNPTG protein. Analysis of the sequences surrounding the microdeletion breakpoints revealed either intrinsic repetitivity of the deleted region or short direct repeats adjacent to the breakpoint junctions. This is consistent with these repeats having mediated the microdeletions via replication slippage and supports the view that the mutational spectrum of the GNPTG gene is strongly influenced by the properties of the local DNA sequence environment.
[ "Identification", "and", "molecular", "characterization", "of", "six", "novel", "mutations", "in", "the", "UDP-N-acetylglucosamine-1-phosphotransferase", "gamma", "subunit", "(", "GNPTG", ")", "gene", "in", "patients", "with", "mucolipidosis", "III", "gamma", ".", "Mucolipidosis", "type", "III", "(", "MLIII", ")", "is", "an", "autosomal", "recessive", "disorder", "affecting", "lysosomal", "hydrolase", "trafficking", ".", "In", "a", "study", "of", "10", "patients", "from", "seven", "families", "with", "a", "clinical", "phenotype", "and", "enzymatic", "diagnosis", "of", "MLIII", ",", "six", "novel", "GNPTG", "gene", "mutations", "were", "identified", ".", "These", "included", "missense", "(", "p.T286M", ")", "and", "nonsense", "(", "p.W111X", ")", "mutations", "and", "a", "transition", "in", "the", "obligate", "AG-dinucleotide", "of", "the", "intron", "8", "acceptor", "splice", "site", "(", "c.610-2A", ">", "G", ")", ".", "Three", "microdeletions", "were", "also", "identified", ",", "two", "of", "which", "(", "c.611delG", "and", "c.640_667del28", ")", "were", "located", "within", "the", "coding", "region", "whereas", "one", "(", "c.609+28_610-16del", ")", "was", "located", "entirely", "within", "intron", "8", ".", "RT-PCR", "analysis", "of", "the", "c.610-2A", ">", "G", "transition", "demonstrated", "that", "the", "change", "altered", "splicing", ",", "leading", "to", "the", "production", "of", "two", "distinct", "aberrantly", "spliced", "forms", ",", "viz", ".", "the", "skipping", "of", "exon", "9", "(", "p.G204_K247del", ")", "or", "the", "retention", "of", "introns", "8", "and", "9", "(", "p.G204VfsX28", ")", ".", "RT-PCR", "analysis", ",", "performed", "on", "a", "patient", "homozygous", "for", "the", "intronic", "deletion", "(", "c.609+28_610-16del", ")", ",", "failed", "to", "detect", "any", "GNPTG", "RNA", "transcripts", ".", "To", "determine", "whether", "c.609+28_610-16del", "allele-derived", "transcripts", "were", "subject", "to", "nonsense-mediated", "mRNA", "decay", "(", "NMD", ")", ",", "patient", "fibroblasts", "were", "incubated", "with", "the", "protein", "synthesis", "inhibitor", "anisomycin", ".", "An", "RT-PCR", "fragment", "retaining", "43", "bp", "of", "intron", "8", "was", "consistently", "detected", "suggesting", "that", "the", "33-bp", "genomic", "deletion", "had", "elicited", "NMD", ".", "Quantitative", "real-time", "PCR", "and", "GNPTG", "western", "blot", "analysis", "confirmed", "that", "the", "homozygous", "microdeletion", "p.G204VfsX17", "had", "elicited", "NMD", "resulting", "in", "failure", "to", "synthesize", "GNPTG", "protein", ".", "Analysis", "of", "the", "sequences", "surrounding", "the", "microdeletion", "breakpoints", "revealed", "either", "intrinsic", "repetitivity", "of", "the", "deleted", "region", "or", "short", "direct", "repeats", "adjacent", "to", "the", "breakpoint", "junctions", ".", "This", "is", "consistent", "with", "these", "repeats", "having", "mediated", "the", "microdeletions", "via", "replication", "slippage", "and", "supports", "the", "view", "that", "the", "mutational", "spectrum", "of", "the", "GNPTG", "gene", "is", "strongly", "influenced", "by", "the", "properties", "of", "the", "local", "DNA", "sequence", "environment", "." ]
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21059483
The GALT rush: high carrier frequency of an unusual deletion mutation of the GALT gene in the Ashkenazi population. Classic galactosemia is an autosomal recessive disorder of galactose metabolism manifesting in the first weeks of life following exposure to a milk-based diet. Despite the benefit of avoidance of lactose, many patients suffer from long-term complications including neurological deficits and ovarian failure. To date, over 230 mutations have been described in the GALT gene resulting in galactosemia. Recently, an unusual mutation was characterized causing a 5.5 kb deletion, with a relatively high carrier rate in subjects of Ashkenazi Jewish (AJ) descent. The aim of this study was to estimate the carrier frequency of this mutation in the AJ population in Israel. For this purpose we developed a high-throughput methodology to genotype both normal and deleted alleles using a chip-based matrix-assisted laser desorption-time-of-flight (MALDI-TOF) mass spectrometer and Multiplex PCR. DNA samples of 760 anonymous AJ subjects were submitted for analysis, subsequently detecting six individuals heterozygous for the GALT deletion mutation, giving a carrier frequency of 1 in 127 (0.79%). Based on these results, we suggest that the method described here provides a basis for genetic screening and prenatal counseling and can potentially reduce the morbidity and mortality associated with delayed diagnosis of galactosemia in this patient population.
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